Hodgkin’s lymphoma was first described by Thomas Hodgkin a century ago and is still referred to by its name when it was considered incurable. early 20th century radiation therapy was discovered and certain patients achieved long-term survival without lymphoma recurrence, which we currently call early stage Hodgkin’s lymphoma. the concept of Hodgkin’s lymphoma staging was further established at the Ann Arbor meeting in 1971. Whereas dissection was once used to determine the extent of a patient’s early stage Hodgkin’s lymphoma (i.e., stages I and II), dissection for Hodgkin’s lymphoma staging is now a thing of the past, with the aid of imaging techniques and effective systemic treatment regimens.
In the 1940s, studies of the application of nitrogen mustard showed that patients with Hodgkin’s lymphoma still had a fairly high response rate to systemic antineoplastic agents. After the discovery of many other active antineoplastic agents, researchers at the National Cancer Institute applied a combination of four antineoplastic agents for the initial treatment of patients with disseminated Hodgkin’s lymphoma. a report of the results published in 1970 clearly showed that treatment of Hodgkin’s lymphoma with chemotherapy alone was possible. Results of studies of adjuvant chemotherapy following radiation therapy for high-risk early-stage Hodgkin’s lymphoma showed a reduced risk of disease recurrence; subsequent studies investigated the efficacy of chemotherapy followed by more modest radiation therapy.
In the 1970s, Ugandan researchers studied the treatment of childhood and young adult Burkitt’s lymphoma, as well as early-stage Hodgkin’s lymphoma, but they did not have radiation therapy techniques. The results of these studies showed that chemotherapy alone could produce high complete and durable remissions in patients with early stage Hodgkin’s lymphoma. Patients with early-stage Hodgkin’s lymphoma are receiving newer treatment regimens, and a series of studies aimed at treatment regimens with less or no radiation and a reduced number of chemotherapy sessions have deepened the understanding of the long-term, toxic response to treatment, and very high survival rates. In the current issue of the journal, Engelert et al. report on a large German clinical trial study investigating the therapeutic effects of reducing the number of treatment courses of adriamycin, bleomycin, vincristine, and dacarbazine (ABVD) alone or in combination with a reduced dose of radiation therapy.
Patients with early stage Hodgkin’s lymphoma are heterogeneous, and the toxic response to treatment varies depending on the type of chemotherapy combination drug and the variability of radiotherapy technique. However, some of the most severe treatment toxicities tend to occur later, after most patient deaths are attributable to lymphoma. These factors make it difficult to determine what regimens are appropriate to recommend for the treatment of patients with early-stage Hodgkin lymphoma.
Risk variables.
Not all early-stage Hodgkin’s lymphoma is the same. As defined by the Ann Arbor Conference (Stage I Hodgkin lymphoma: involvement of one lymph node with or without spread to adjacent extra-nodal sites; Stage II Hodgkin lymphoma: involvement of 2 or more lymph nodes in the ipsilateral mediastinum with or without spread to adjacent extra-nodal sites.) The prognosis of patients with stage I and stage II Hodgkin’s lymphoma varies widely. Many factors can worsen the prognosis of these patients, including the presence of systemic symptoms (i.e., fever, night sweats, significant wasting), a high erythrocyte sedimentation rate, an increased number of involved lymph nodes, older age, and a widened mediastinum. It is on the basis of different combinations of these or those risk factors that this is therefore the rationale for stratified randomization in most clinical trials of early-stage Hodgkin lymphoma. Now, of course, not everyone agrees with the staging of Hodgkin’s lymphoma.
The importance of treatment-related complications.
Regardless of the stage of Hodgkin’s lymphoma patients, the primary treatment goal is cure. Recent clinical trial studies.
Patients with early-stage Hodgkin lymphoma have consistently achieved 5-year survival rates of 90 percent or better. In particular, the number of patients in the pilot study who had a good prognosis through a long follow-up period died from treatment-related complications more often than from Hodgkin’s lymphoma itself.10 The frequency of late complications varies depending on the specific treatment regimen used. Radiation therapy-related late complications have been studied quite extensively. Together with the fact that late complications associated with radiation therapy can affect the quality of life of patients but are not likely to be fatal (e.g., hypothyroidism, dry mouth, and dental caries), the incidence of many potentially fatal events increases after radiation therapy. At least 30 years after treatment, the average annual rate of occurrence of a second worsening is approximately 1%. This risk is particularly high in women younger than 30 years of age treated with chest radiation; 25 years after radiation therapy, these patients have a 30 to 40 percent chance of developing breast cancer. It seems intuitively obvious to think that lowering the radionuclide dose and the size of the exposure will likely reduce the incidence of second progression, and the combination of case-control study results suggests that this may indeed be the case. However, the relatively short follow-up periods of most clinical trial studies have resulted in a lack of evidence of a definite association between radionuclide dose and cancer incidence, making definitive conclusions impossible. Cardiac diseases associated with radiation therapy manifest as coronary artery disease, myocardial damage, valvular disease, and pericardial fibrosis. The increased risk of death from myocardial infarction occurs after chest radiation therapy, with the increased risk lasting even more than 25 years. and after radiation therapy, diastolic dysfunction appears to be a marker of increased risk of cardiovascular events. Patients who receive radiation therapy to the neck and mediastinum also have an increased incidence of stroke in patients.
= The risk of developing late complications with chemotherapy appears to be associated with the type of chemotherapeutic agent used. For example, patients whose regimens included nitrogen mustard were at significantly increased risk for spinal cord dysplasia, acute myeloid leukemia, and lung cancer. However, patients in the pilot study who received nitrogen mustard phenylbutyrate, but not nitrogen mustard, did not have an increased risk of lung cancer. Patients were at increased risk of spinal cord dysplasia, acute myeloid leukemia if their treatment regimen included alkylating agents or etoposide, and patients receiving MOPP regimens (i.e., nitrogen mustard, vincristine, methylphenidate, and prednisone) with a 2% to 5% incidence of these complications. Common ABVD regimens include adriamycin, which is associated with an increased risk of congestive heart failure, and combination radiotherapy and mitoxantrone chemotherapy, which have an increased frequency of cardiovascular events.ABVD regimens also include bleomycin, which is associated with the development of pulmonary fibrosis. Acute lung injury associated with bleomycin is fatal; monitoring of diffusion function of the lung is often required to prevent the onset of acute lung injury.
A prospective international randomized trial study of quality-of-life treatment effects in patients with Hodgkin’s lymphoma in which subjects were treated with radiotherapy, combined with or without chemotherapy. Although, treatment usually had a significant adverse effect on quality of life in all patients, there was no statistically significant correlation between patients’ quality of life and the type of treatment regimen.
Treatment strategy.
Based on many clinical trial studies (which used different definitions for low and high risk, which could potentially influence the judging of trial results.) The results found, that many researchers are very concerned about the correlation, between the type of treatment regimen or strategy and the risk of treatment failure. First, there were very high survival rates – 5-year survival rates of 90% or higher – in all clinical trial studies, with the exception of one clinical trial in which patients receiving combination chemotherapy regimens had significantly lower treatment outcomes than those reported in other clinical trial studies. Receiving a single treatment regimen (especially radiation therapy) rather than a combination regimen appears to have a higher recurrence rate. Although, effective salvage regimens can be utilized to achieve equivalent survival rates, the exception is: in the longest follow-up period study, patients receiving a single radiation regimen had a lower 25-year survival rate compared to those treated with a MOPP regimen. In both the low-risk and high-risk groups in all clinical trial studies, fewer patients died from Hodgkin’s lymphoma per se than from other causes. However, only one of these clinical trial studies had a median follow-up period of more than 10 years. Thus, although, the trial results reflect that most deaths were associated with Hodgkin’s lymphoma itself, the true number of deaths from other causes such as second worsening events or cardiovascular events may have occurred after a median follow-up period of 10 years.
Special considerations.
Patients with early stage Hodgkin’s lymphoma are associated with many other complications, such as including patient pregnancy, older age, infection with human immunodeficiency virus (HIV), and nodular lymphocyte-dominant Hodgkin’s lymphoma.
Pregnancy.
If the chances of Hodgkin’s lymphoma in young adults are quite high, it is not surprising that it is found during pregnancy as one of the higher incidence of worsening events. Patients with Hodgkin’s lymphoma in pregnancy need to avoid, to some extent, the use of computed tomography (CT) and positron emission tomography (PET) for attempts to stage the disease, but abdominal ultrasound can be used to detect disease below the diaphragm. Pregnant patients with asymptomatic early stage Hodgkin’s lymphoma are sometimes, treated only after delivery. Although, radiotherapy should be avoided during pregnancy, treatment in combination with ABVD chemotherapy regimens in mid and late pregnancy is relatively safe. Treatment with vincristine alone in targeted patients can help control Hodgkin’s lymphoma symptoms until delivery, after which standardized treatment is necessary. Treatment of patients with Hodgkin’s lymphoma in the first trimester of pregnancy is a very difficult problem. If treatment is necessary and the patient does not want to terminate the pregnancy, patients treated with ABVD regimens or similar regimens may successfully complete the pregnancy without fetal malformations.
Older age.
Patients with Hodgkin lymphoma who are 45 to 50 years of age or older have a poor prognosis compared to younger Hodgkin lymphoma patients, especially those who are 60 years of age or older. One reason for the relatively poor prognosis of some patients is that patients are sensitive to drug toxicity from intensive treatment regimens. For example, the results of a pilot study showed that elderly patients treated with expanded radiotherapy had a significantly worse prognosis compared to local tumor radiotherapy only; this was not observed in younger patients treated. Older patients are more likely to have acute toxic reactions, higher recurrence rates, and lower overall survival rates. Older patients are less likely to be studied in clinical trials because they often have other coexisting conditions that affect their ability to tolerate standard therapy. It has been argued that the nature of Hodgkin’s lymphoma in the elderly is different from that of Hodgkin’s lymphoma in the young. In fact, it is suggested that older Hodgkin’s lymphoma be classified as a special type of lymphoma, and that unusual disease deserves special study in clinical trial studies.
However, in general, healthy older patients should receive and benefit from treatment regimens that are effective in younger patients. Older patients appear to benefit at a greater rate than younger patients with adriamycin-containing regimens.
Human immunodeficiency virus infection.
Hodgkin’s lymphoma is one of the diseases defined by the human immunodeficiency syndrome (AIDS). Patients with Hodgkin’s lymphoma with HIV infection form a typical mixed cell nature or lymphocyte-deficient tissue subtype, and they have a tendency to spread the disease, involve extra-nodal sites and have systemic symptoms. More aggressive and effective antiretroviral therapy in patients with Hodgkin’s lymphoma with HIV infection can significantly improve patient survival. Currently, patients with early-stage Hodgkin lymphoma with HIV infection should be treated with the same regimen as patients with early-stage Hodgkin lymphoma without HIV infection.
Patients with nodular lymphocyte-predominant Hodgkin lymphoma25 and a diagnosis of Hodgkin lymphoma are typical in at least 95% of cases, not patients with nodular lymphocyte-predominant Hodgkin lymphoma. Nodular lymphocyte-predominant Hodgkin’s lymphoma is a type of hypodifferentiated, monoclonal B lymphocyte that often presents early as malignant. As with other poorly differentiated B lymphocytic tumors, nodular lymphocyte-dominant Hodgkin lymphoma can transform into disseminated large B lymphocytic lymphoma. Patients with early stage nodular lymphocytic predominant Hodgkin’s lymphoma can be treated with clinical observation, radiotherapy, combination radiotherapy, monotherapy, or with rituximab (or melphalan, rituximab,, rtx, a genetically engineered chimeric anti-CD20 monoclonal antibody). Patients with early-stage nodal lymphocyte-dominant Hodgkin’s lymphoma appear to have a treatment regimen that includes radiation therapy that is particularly important and induces durable remission.
Treatment options.
The preferred treatment option for patients with early-stage Hodgkin’s lymphoma is not yet recognized. The use of effective treatment regimens alone (e.g., ABVD) or various combinations of chemotherapy and radiotherapy are associated with high overall survival rates. The fact is that adverse treatment-related events that continue to occur 20 to 30 years after treatment (with a steadily increasing frequency in some cases) can be fatal; recent clinical studies suggest that a median follow-up period of less than 20 years makes it difficult to choose a treatment option. Oncologists are conducting studies on recommended treatment options for patients with early-stage Hodgkin lymphoma, but their findings are also not particularly exciting. Radiation therapy oncologists, more than medical oncologists, are more likely to recommend the use of radiation therapy. Oncologists with long practice experience have witnessed more late complications of treatment and are less likely to recommend radiation therapy as strongly as radiation therapy oncologists. Internal medicine specialists treating female Hodgkin’s lymphoma patients are more likely to choose single chemotherapy and treating older patients are likely to choose combination therapy regimens. It appears that the actual recommended treatment regimen is heavily influenced by the preferences and accumulated clinical experience of medical specialists with particular treatment options – and is not based on the published literature.
The 5-year survival rate for patients with early-stage Hodgkin’s lymphoma treated with current treatment regimens exceeds 90%. Patients with poor prognosis have a slightly lower overall survival rate – and a slightly higher relapse rate – but more intensive treatment regimens will increase the risk of death. It is more likely that patients receiving combination regimens have a higher risk of death; however, in a clinical trial study, the 5-year survival rate for patients treated with ABVD chemotherapy alone was 95 percent. ABVD is clearly the best choice when treated with chemotherapy alone or in combination with radiotherapy. Because, with one exception, the longest median follow-up period in all clinical trial studies did not exceed 10 years, most late treatment-related deaths have not yet occurred, and the benefits of ABVD chemotherapy alone will likely be apparent at longer follow-up periods. However, even at short follow-up periods, the number of treatment-related deaths in patients with Hodgkin’s lymphoma is much higher than the number of deaths due to Hodgkin’s lymphoma disease itself. Of the low-risk patients exemplified in Table 2, clinical trial studies reported that 27 died from Hodgkin’s lymphoma disease itself and 76 died from other causes.
In the United States, oncologists often refer to the National Comprehensive Cancer Network guidelines when selecting treatment options. These guidelines recommend that in patients with asymptomatic, modestly sized early-stage Hodgkin lymphoma with an erythrocyte sedimentation rate <50 mm/hour, fewer than four involved lymph nodes, and no more than one site of extra-nodal spread, internists should treat with ABVD chemotherapy alone or in combination including either ABVD chemotherapy alone or the Stanford V chemotherapy regimen (nitrogen mustard, adriamycin, etoposide, vincristine, vincristine bleomycin, and prednisone), plus local lesion radiotherapy. Patients at increased risk of initial treatment failure also include either ABVD chemotherapy alone or Stanford V chemotherapy regimens, however, if the patient has a large tumor size they should all be treated with combined localized focal radiotherapy. If patients are at increased risk of treatment failure but have small tumors they can be treated with ABVD alone, however, they should receive a minimum of 6 courses of therapy rather than 4 courses of therapy, which is the minimum treatment requirement for patients without risk. In patients who achieve a complete response after 2 courses of chemotherapy with ABVD alone or at least 12 weeks of treatment with the Stanford V chemotherapy regimen, each subgroup, the choice of subsequent treatment regimen is determined based on the results of early positron emission tomography scans.
Treatment plans for subgroups of Hodgkin lymphoma patients in an ongoing series of international clinical trial studies.
A new clinical trial study for the treatment of patients with early stage Hodgkin’s lymphoma. The basic aim of the study is to attempt to minimize the number of treatment regimens needed for personalized treatment and cure using positron emission tomography. Apparently a positive PET finding at the end of the treatment period is an obvious unfavorable risk factor. After a total of 73 patients completed ABVD chemotherapy as the first phase of a combined radiotherapy regimen, 13 of them had positive PET scan findings. 2-year chemotherapy failure-free survival was 69% for PET scan-positive patients and 95% for PET scan-negative patients. However, 46 patients had interim PET scans (after completion of 2-3 courses of chemotherapy), of which 20 patients had positive interim PET scans, but 13 patients with PET scans at the completion of chemotherapy turned negative. The 2-year chemo-failure-free survival rate was 92% for patients with positive PET scans during chemotherapy and negative PET scans after completion of chemotherapy, and 96% for patients with negative PET scans both during and after chemotherapy. A series of patients treated with ABVD chemotherapy alone and scheduled for 6 courses of chemotherapy had a progression-free survival rate of 71% for positive PET scans after completing 2 to 3 courses, compared with 90% for patients with negative interim PET scans. Although, if a patient has a positive mid-term PET scan and a negative PET scan after completing 6 courses of ABVD chemotherapy treatment, the unfavorable risk factors for a positive mid-term PET scan disappear. Therefore, a positive interim PET scan need not be used to predict a patient’s adverse treatment prognosis, because the relapse rate in patients with a positive interim PET scan and a negative PET scan after completion of ABVD chemotherapy treatment is unlikely to exceed the relapse rate in patients with a negative interim PET scan and a negative PET scan after completion of chemotherapy treatment. Was the treatment regimen adjusted based on a positive but improving interim PET scan profile? The question of whether the patient ultimately benefits without continued treatment to achieve complete remission? Further clinical trial studies are needed to confirm this; in this instance, such a regimen should not be used as the standard of care.
Conclusion.
The treatment of patients with early stage Hodgkin’s lymphoma is one of the modern oncology treatment success stories. These patients now have a survival rate of >90% at least 5 years after diagnosis, regardless of their respective characteristic presentation, and treatment outcomes are so good that current clinical trial studies, focus only on minimizing the intensity of treatment regimens to avoid late and potentially fatal toxic reactions. Patients with low-risk early-stage Hodgkin lymphoma can achieve equivalent survival with standard chemotherapy regimens alone and the application of fewer courses of chemotherapy plus focal tumor radiotherapy; patients with high-risk early-stage Hodgkin lymphoma can also be treated with such regimens. If less intensive regimens are favored, it is important to observe to determine which regimen is flawed and which regimen will begin to increase the number of deaths in patients with Hodgkin lymphoma. For example, clinical trials conducted by the German Hodgkin’s Lymphoma Study Group studied that patients with high-risk Hodgkin’s lymphoma treated with ABVD chemotherapy and 20 gorey doses of local lesion radiotherapy were less effective than those treated with not the same doses of ABVD chemotherapy and 30 gorey doses of local lesion radiotherapy, or more intensive chemotherapy regimens [i.e., bleomycin, cyclophosphamide, adriamycin, etoposide prednisone, methylbenzylhydrazine, and vincristine (BEACOPP) and a 20-goride dose of local focal radiotherapy treatment was effective. However, patients treated with regimens that include radiation therapy have a higher rate of long-term complications compared to patients treated with chemotherapy regimens alone, which may ultimately lead to lower long-term survival, especially in patients with low-risk Hodgkin’s lymphoma. (Publication of many ongoing clinical trial studies: the effect of short-term ABVD chemotherapy alone compared to the therapeutic effect of combined ABVD chemotherapy and radiotherapy).
Dr. Armitage serves on the Board of MGI Pharmaceuticals (North American subsidiary of Eisai) and the Roche Anemia Research Foundation; receives consultant fees from Alos Therapeutics, Ziopharm, Biogen, IDEC, Eisai, Amgen, L’Oreal, and the French Hodgkin Lymphoma Collaborative Group. Participated in educational activities and received speaker fees from Imedex, Clinical Health Options, PRIME (Pioneer) Cancerology, and the Institute for Medical Education and Research.