Low-grade non-Hodgkin’s lymphoma (NHL) is an indolent form of the disease with a generally slow course of progression. Although still usually incurable, low-grade disease has shown responsiveness to some of the newer
Low-grade non-Hodgkin’s lymphoma (NHL) is an indolent form of the disease with a generally slow course of progression. Although still usually incurable, low-grade disease has shown responsiveness to some of the newer chemotherapeutic and nonchemotherapeutic treatment options. However, since cure remains elusive, and since many patients with low-grade NHL may have few or even no symptoms initially, the decision about whether or not to initiate treatment logically must include quality-of-life (QOL) issues. This paper summarizes clinical and diagnostic characteristics of low-grade NHL that have some bearing on QOL considerations. Adverse effects of the more common treatment approaches are discussed according to their QOL implications, illustrating the relevance of QOL to the clinical management of low-grade disease. Finally, data from an ongoing study using the Functional Assessment of Cancer Therapy (FACT) measurement system are presented. These data offer a basis for comparing the QOL of patients with NHL to that of individuals with other solid tumors, and also illustrate the effects of chemotherapy on QOL.[ONCOLOGY 12(5): 697-717, 1998]
In 1997, an estimated 54,000 people in the United States were diagnosed with non-Hodgkin’s lymphoma (NHL). This disease thus accounted for nearly 4% of cancer incidence overall. In the same year (1997), almost 24,000 people died of the disease.
The subclassification of low-grade NHL constitutes approximately 25% of all cases. Incidence of low-grade disease is higher in people between the ages of 35 and 64 years (37%) than in those under age 35 (16%). Ironically termed the “favorable” or indolent form of NHL due to a natural history characterized by slow disease progression and a relatively long duration of survival (7 to 10 years) when compared to intermediate- and high-grade disease, low-grade NHL is still regarded as essentially incurable.[5,6]
The addition of new treatment options, a better understanding of factors that predict response, and the introduction of new nonchemotherapeutic therapies have improved the clinical management of low-grade NHL. These improvements have not yet produced a significant increase in cure rate, however.[7-9] For this reason, and because life-extending treatments produce toxicity and added cost, quality of life (QOL) emerges as a very relevant consideration when judging therapeutic benefit.
The course of progressive low-grade NHL is typified by sequential remissions and relapses, disease dissemination, and eventual resistance to current treatment approaches. Also, since patients often opt for alternative treatments at times of relapse, they are likely to endure acute and chronic treatment toxicity, as well as psychosocial sequelae associated with chronic, life-threatening disease.
In summary, given that the disease produces symptoms, the chance for cure is low, and available treatments have a questionable impact on survival and known toxicity (or cost), QOL may be the most important clinical management concern. To date, however, there has been a paucity of relevant literature and research on the quality of life of patients with low-grade lymphoma, and no published randomized clinical trial has included QOL evaluation as an outcome. The need for reliable, valid measures of the physical, functional, emotional, and social impact of lymphoma is apparent. Although questionnaires that measure general QOL are available,[10-12] there is no lymphoma-specific QOL questionnaire or subscale that addresses the particular symptoms or concerns of patients with lymphoma or the effects of lymphoma treatments on life quality. Treatment decision-making (by both patient and physician) and practice guidelines would be enhanced by the ability to balance QOL consequences against the known benefits and drawbacks of established and investigational treatments, such as extension of survival time, durability of remission, toxicity of treatment, and effectiveness of palliation.
This paper will summarize the clinical characteristics of low-grade NHL, including classification, staging, and symptoms, as well as the predictors of treatment response. Adverse effects of the most common treatments and their QOL implications will also be discussed, in an attempt to illustrate the high degree of relevance of QOL considerations to clinical management. In addition, the psychosocial sequelae of NHL will be reviewed. Finally, data derived from a commonly used questionnaire, the Functional Assessment of Cancer Therapy (FACT) measurement system, will be presented. These data were used to compare the QOL of patients with NHL to a matched sample of patients with mixed cancer types and a smaller sample of patients with Hodgkin’s disease; the QOL of NHL patients according to treatment status (on vs off chemotherapy) were also compared.
Classification and Staging
Non-Hodgkin’s lymphomas comprise a wide range of malignancies that originate in the lymphoid system. They differ according to their pathologic and immunologic characteristics and their prognostic classification.[3,5,6] Efforts have been made to create a taxonomy that effectively groups all lymphomas into distinct categories according to their morphology, course, and outcome. Due to the variability of lymphomas, however, development of a pure classification system still remains challenging.
At present, NHLs are commonly classified by the International Working Formulation, established in 1982 by a special task force of the National Cancer Institute to consolidate lymphomas by clinically useful criteria so as to predict biological behavior, curability, and survival. Another classification system, the revised European-American classification of lymphoid neoplasms (REAL) has been proposed but is not universally accepted. Precise diagnostic evaluation of the histologic subtype and classification have become critical for appropriate management of the disease.
The International Working Formulation defines three general categories of lymphomas-low grade, intermediate grade, and high grade-which are differentiated most notably by their aggressiveness or “malignant potential.” Low-grade lymphomas include small lymphocytic; follicular, small cleaved cell; and follicular, mixed, small cleaved and large cell subtypes, which are indolent by nature and initially responsive to a variety of treatments but eventually prove nonresponsive.
Non Hodgkin’s lymphoma is clinically staged using the Ann Arbor staging classification (stage I, II, III, IV), which indicates the extent to which lymph node regions and extralymphatic sites are involved.
An unusual increase in the incidence of NHL since the 1970s, combined with little improvement in relative survival rates, continues to challenge the medical community, despite the availability of diverse treatment options. Risk factors associated with low-grade lymphomas include increasing age, male gender, exposure to chemotherapy and radiation, and chronic immunosuppression.[3,5] Of particular importance to QOL are practice guidelines based on poor prognostic factors, such as age.
Diagnostic procedures to determine the type of lymphoma and extent of disease are quite extensive, and often require that patients undergo a variety of invasive and noninvasive tests, procedures, and surgical explorations. Physical examination, peripheral lymph node biopsies, chest x-rays, computed tomographic (CT) scans, bilateral bone marrow biopsy, spinal taps, blood tests, and surgical evaluation of tissue and organ involvement collectively lead to an accurate diagnosis.[3,5]
Repeat assessments are necessary to determine response to treatment and guide therapeutic decisions. Chronic invasive assessments in patients with hematologic malignancies cause discomfort and are associated with heightened anxiety, especially at follow-up visits, where fear of recurrence may be confirmed.
Disease symptoms include both common lymphoma symptoms that are indicative of active disease and specific symptoms highly influenced by the location(s) and extent of disease dissemination. The majority of patients present initially with asymptomatic adenopathy (lymph node swelling) and may have active disease without symptoms for up to 3 years after diagnosis, making early treatment (for some) optional. The indolent nature of the low-grade subtypes may also allow some patients to live a relatively prolonged symptom-free and active life until the disease progresses.
Nonspecific lymphoma symptoms, commonly referred to as B symptoms, include fatigue, fever, weight loss, and drenching night sweats. These symptoms are prognostically unfavorable and therefore are often an indication for treatment. Other relevant symptoms include pain and cosmetic problems due to enlarged lymph nodes.
Independent of prognostic differences, treatment of symptomatic disease is more easily justifiable than treatment of asymptomatic disease, on QOL grounds. This will be addressed below.
Site-specific involvement can be limited or widespread, can occur anywhere in the lymphatic system (eg, lymph nodes, spleen, and bone marrow), and can spread to one or more extralymphatic organs (eg, stomach, intestine, bone, skin, oral cavity, and pharynx).[3,5] The presence of bulky masses causes discomfort and often pain.
Other symptoms vary and may include abdominal pain, ulcers, or bleeding if the gastrointestinal (GI) tract is involved. If there is throat or sinus involvement, head and neck discomfort, throat pain, or swallowing difficulty can occur. Patients with neurologic or musculoskeletal system involvement may experience neurologic and musculoskeletal pain and muscle weakness. With bone marrow involvement, weakened immunity or chronic infections can develop.
In short, the range of possible symptoms and functional problems associated with low-grade NHL is diverse, and depends on the site and degree of involvement. Progressive disease dissemination to additional sites places patients at increased risk for new symptoms and problems, which are often unpredictable, although manageable with palliative therapies.
A great deal of attention has focused on evaluating predictors of treatment response and overall survival in order to optimize treatment selection.[18-22] Histologic subtype, disease stage, prior treatment, and age are often cited as determinants of treatment selection.[7,23,24] The presence of B symptoms, age greater than 65 years, poor performance status, high serum lactic dehydrogenase (LDH) levels, number of nodes involved, number of sites involved, intraabdominal involvement, immunoglobulin level, advanced (stage III/IV) disease, and histologic transformation to intermediate- or high-grade disease have been identified as factors that adversely affect survival.[18-22] These factors may also have important QOL implications, especially if they contribute to a significant decrease in physical well-being and functioning or preclude further treatment.
Histologic transformation to intermediate- or high-grade lymphoma has been observed in the natural course of untreated lymphoma and in patients who have received prior therapy. Generally, transformation to higher-grade disease is an unfavorable sign, although there is a subset of patients who have responded well to additional therapy and have enjoyed relatively long-term survival. Fear of histologic transformation (increasing aggressiveness and potential fatality of the disease) is an uncertainty that many patients with low-grade lymphoma must face.
In addition, the risk of developing a second malignancy has been shown to be higher (21%) in long-term NHL survivors (3 to 20 years), as compared with the estimated cumulative risk in the general population (15%). This increased risk is believed to be related, in part, to immunosuppression and exposure to radiation therapy and chemotherapy.
Treatment of low-grade lymphoma continues to challenge physicians, who essentially are managing a chronic, incurable disease over many years. With the exception of some patients with localized stage I lymphomas treated with radiation and some stage II patients treated with combined chemotherapy and radiation, to date there is little evidence confirming that the type of treatment administered has a significant bearing on overall survival.[9,27] In addition, the advantages of early or aggressive treatment and its impact on overall survival have not been clearly demonstrated.[28,29] However, several treatment options are available with varying toxicity and QOL trade-offs: radiation therapy, alone or combined with chemotherapy, single-agent chemotherapy (oral and injectable), combination chemotherapies, bone marrow transplantation (BMT), monoclonal antibodies, and maintenance therapies.
Standard treatment guidelines for low-grade lymphomas have been difficult to create given the diversity and relative safety and efficacy of available treatments, the wide range of currently identified prognostic factors, and the opportunity for participation in new clinical trials. Although patients may benefit from many therapies, selecting optimal treatment approaches throughout the course of the disease can involve risks (perceived and actual) and trade-offs. For example, patients whose lymphoma is not treated initially may feel uneasy about not actively fighting the disease. Conversely, patients who pursue initial aggressive treatment may endure debilitating, even life-threatening side effects with long-term QOL consequences for an unknown potential advantage.
The lack of clinical trial data on QOL creates obstacles to deciding among various treatment options, especially with regard to early or aggressive therapies that have not been shown to benefit the traditionally most important outcome (overall survival). The degree to which patients are involved in this decision-making process is unclear, and probably depends somewhat on patient attitude and pursuit of information, as well as physician approach, ability, and interest in summarizing and communicating information about the trade-offs between treatment toxicities and probability of benefit. Although it is often helpful for patients to research and learn about their disease and exercise control over treatment choices, repeated involvement and informed consent to treatments that essentially involve a progressive gamble can be emotionally burdensome.
Watchful Waiting vs Active Treatment-The “watch-and-wait” approach established by the Stanford group in the early 1980s is a conservative approach to the treatment of a select group of patients with newly diagnosed low-grade NHL. Investigators have shown that watchful waiting for disease progression or symptoms before initiating therapy does not adversely affect overall survival. For some patients, a high level of physical and functional QOL may be maintained for 3 or more years due to the fact that they are asymptomatic, may have spontaneous disease regression, and are not subject to the toxicities of induction or maintenance therapies. However, because these clinically logical conclusions were not demonstrated with formal QOL assessment, little is known about the emotional and social well-being of patients who defer treatment.
Quality-of-life implications for patients receiving active treatment depend, in part, on the type of therapy, method and frequency of delivery, and the availability and use of supportive agents to counter side effects. Frequently, chemotherapy for NHL is myelotoxic, compromising an already deficient immune system. The addition of radiation therapy, other alkylating agents, or biological response modifiers can significantly contribute to the problem. For example, the combination of chemotherapy and total-body irradiation may lead to acute bone marrow suppression, and the addition of interferon to chemotherapy may result in debilitating side effects, such as fatigue.
Because there are no formal QOL data from randomized clinical trials of low-grade lymphoma patients, we can only estimate the impact of previously studied treatments on QOL by treating toxicity data as a proxy for QOL assessment. Naturally, this must be done with caution because the provider is the source of toxicity data, whereas the patient is the source of QOL data. Also, toxicity data cover only some of the treatment-related QOL problems that patients can have.
Radiation therapy has been shown to produce significant, possibly curative results in a subgroup of patients with early-stage (I or II) localized low-grade lymphoma. Except for palliative reduction of bulky disease, radiation therapy is not commonly used in the management of advanced disease. Localized radiotherapy (involved-field, extended-field, or total lymphoid irradiation) usually does not yield serious toxicities. Skin sensitivity and dryness are common problems at local sites.
When combined with chemotherapy in any stage of disease, radiation therapy may cause pneumonitis, myocardial toxicity, side effects specific to the radiation site, gonadal dysfunction, and sterility. When radiation therapy is used for palliative reduction of bulky disease, its value can be understood as a trade-off between symptomatic relief and treatment toxicity, since survival is not altered.
Both single chemotherapeutic agents and multidrug combinations have been used in the treatment of low-grade NHL.
Single Agents-Single-agent therapies, such as chlorambucil (Leukeran) and cyclophosphamide (Cytoxan, Neosar), have been shown to yield similar responses to more aggressive multidrug regimens in their impact on overall survival and are generally less toxic.[34,35] In clinical trials of each drug, most patients experienced treatment-related toxicities, including nausea/vomiting/anorexia and/or diarrhea (31%), GI symptoms (90%), and leukopenia (58% with cyclophosphamide and 67% with chlorambucil). Thrombocytopenia (43%) was reported with chlorambucil, while hemorrhagic cystitis (37%) and alopecia (26%) were observed with cyclophosphamide.
Combination regimens-such as CVP (cyclophosphamide, vincristine [Oncovin], and prednisone) and CHOP (cyclophosphamide, doxorubicin, Oncovin, and prednisone) often produce more toxic effects, and are accompanied by questionable trade-offs. For example, aggressive front-line treatment does not extend overall survival but has been shown to induce a more rapid response, higher response rate, and longer freedom from disease progression.[28,29,36] Data from trials of CHOP report major hematologic and neurotoxic effects, however, as well as death secondary to therapy.[37,38] Two clinical trials reported fatal toxicities in 1% and 3% of patients and grade 3 or 4 toxicities in 28% and 31%. In other trials, common side effects of CHOP included leukopenia (89% grade 3 or 4), thrombocytopenia (11% grade 3), and anemia (74% grade 3). Neutropenic fevers were common and often led to hospitalization (47%).
Low sperm count and increased risk of infertility in men have also been shown to be consequences of combination chemotherapy. The combination of cisplatin (Platinol) and etoposide yielded serious toxicities when administered to 51 patients; these included hematologic toxicity (39% neutropenia, 35% thrombocytopenia, 16% anemia), severe hemorrhage, and one death due to infection.
Newer aggressive multidrug regimens used in patients with relapsed low-grade lymphoma, such as FMD (fludarabine, mitoxantrone, and dexamethasone) and DHAP (dexamethasone, Ara-C, and Platinol), have been shown to cause severe myelosuppression and secondary opportunistic infections (such as herpes zoster and Pneumocystis infections), bacterial and fungal infections, renal insufficiency, mucositis, and neurologic toxicity.[42,43] Some of these treatments have yielded higher response rates than traditional salvage therapies, but not without cost, functional impairment, and life-threatening toxicity.
Purine Analogs-The relatively new purine analogs have shown promise in low-grade lymphoma and thus provide additional options and challenges for the management of this disease. Fludarabine (Fludara), 2'-deoxycoformycin (pentostatin [Nipent]), and 2-chlorodeoxyadenosine (2-CDA, cladribine [Leustatin]) have demonstrated single-agent antitumor activity, with documented partial and complete response rates and prolonged remissions.[45,46]
The frequency and degree of toxicity reported vary by trial but are consistent with the hematologic side effects of other chemotherapies, and include lymphopenia, leukopenia, neutropenia, thrombocytopenia, opportunistic infections, bacterial and fungal infections, nausea, diarrhea, and peripheral neuropathy.[46-48] Infection-related deaths secondary to treatment have been documented with both fludarabine and cladribine.[48-50] One recent study suggested that dose reductions of standard cladribine treatment can afford patients similar results without the severity of myelotoxicity and infection risk that accompany elevated dose-a meaningful QOL consideration.
The purine analogs are important additions to the spectrum of treatment options. These agents have received a great deal of attention recently due not only to their value as effective anticancer drugs but also to their ability to invoke remissions in previously treated and older patients.
Bone Marrow Transplantation
Interest in evaluating the success of autologous and allogeneic BMT for patients with low-grade lymphoma has paralleled advances in the science of stem-cell transplantation. As is true for most other available treatments, stem-cell transplantation has been shown to prolong failure-free survival, but more mature data are needed to demonstrate any overall survival advantage or curative effect.[52-56] Severe, life-threatening toxicities of myeloablative chemotherapy and radiation therapy are considerable. In one retrospective review of low-grade lymphoma patients, 8% died within 100 days of transplantation.
The QOL consequence of BMT have been studied in patients with mixed cancers (including those with NHL). Although many patients have a good recovery from BMT, the period of convalescence is protracted and may include a prolonged hospital stay in isolation. This can precipitate long-term physical and functional problems. Treatments can also cause gonadal damage and infertility (with their attendant consequences for psychosocial and sexual functioning).
In one study of allogeneic transplantation, 40% of recipients took more than 1 year to return to normal physical and psychosocial functioning and employment status. Another study of patients receiving an allogeneic or autologous transplant demonstrated that a majority of patients experienced physical difficulties (weakness and fatigue), as well as sexual and occupational problems, at more than 12 months post-BMT.
Without demonstrated cure, treatments as intensive as BMT pose a compelling QOL trade-off challenge to low-grade lymphoma patients and their providers with regard to making treatment decisions.
New treatment approaches for low-grade lymphoma include monoclonal antibodies that attach to receptors found on B-lymphocytes. One general approach uses radiolabeled antibodies; another uses a “naked” antibody. Preliminary studies of these monoclonal antibodies as single agents has demonstrated encouraging response rates and some evidence of long-term disease control, but the median duration of response and impact on overall survival are still unknown.
The most frequently observed side effects of monoclonal antibody therapy occur during the infusion and include rigor, fever, chills, nausea, headaches, and hypotension.[60,61] The infusion-related side effects typically diminish in severity with repeated administration.[60,61] Other toxicities include myelosuppression and infections, which occur at a lower rate with naked antibodies than with radiolabeled antibodies.[60,61]
Given the available spectrum of chemotherapy regimens and their toxicities, treatments that have limited and non-life-threatening toxicities, such as monoclonal antibodies, may be relatively more favorable to the QOL of patients who endure repeated treatments and relapses.
Maintenance therapies are also used in the treatment of low-grade lymphoma, and are believed to contribute to the prolongation of relapse-free survival-a meaningful end point given the incurability of the disease.[62,63] Maintenance therapies, such as interferon- alfa-2a (Roferon-A) or interferon-alfa-2b (Intron A) and intermittent CVP, have yielded mixed results with regard to their value and efficacy. Although progression-free survival advantages have been demonstrated, the trade-off of chronic side effects makes the decision of whether to use maintenance therapy a difficult one.
Leukopenia, thrombocytopenia, anemia, vomiting, and neurologic effects were seen in one trial of CVP. Some patients (14%) withdrew from the study and an additional 14% refused further treatment because of side effects.
Interferon as maintenance therapy has also had varied results but is known to cause debilitating fatigue and other flu-like symptoms, which may be of severe consequence to physical well-being and role functioning.[64,65] One study of multiple myeloma patients who received interferon therapy demonstrated that side effects had negative QOL consequences (ie, fatigue and fever had a negative impact on functioning), but for a subgroup of patients, the decrease in life quality was worth even a small survival or disease-free survival benefit.
This finding provides a good argument for the value of further QOL research for treatments (such as interferon) complicated by trade-offs that may vary according to patient preferences. The integration of QOL data and patient preferences, combined with the evaluation of trade-offs, such as with the Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) statistical technique, may further guide the choice of optimal treatment. The concept of a “symptom-free interval,” if developed within the Q-TWiST methodology to include patients with active, essentially asymptomatic disease, could help move this effort forward.
Overall, balancing treatment efficacy and toxicity is important in determining its value. When cure is unlikely or impossible, extending life becomes a valued goal. A treatment that extends life without improving its quality relative to a no-treatment alternative becomes increasingly less valuable as treatment toxicity becomes increasingly more significant.
A great deal of literature is available on the QOL and psychosocial experience of cancer treatment and survivorship, but little pertains specifically to low-grade lymphoma. Hodgkin’s disease has offered investigators a unique opportunity to study QOL and long-term psychosocial adaptation of a group of patients in which the cure rate approaches 90%.[66,67] Quality-of-life research on other tumors, such as lung cancer, provides important information about treatment differences and may have value as a predictive indicator of survival and response to therapy. It has been suggested that this information can be incorporated into practice guidelines to help guide decisions about whether to continue aggressive therapy or switch to palliative care. Patients with low-grade lymphoma are at risk of undergoing repeated aggressive and experimental treatment approaches with questionable trade-offs, may live for protracted periods of time as “survivors” (free of disease), are likely to experience difficulties in psychosocial adaptation to illness and to long-term survivorship, and must contend with the uncertainty of relapses and essential incurability of the disease.
QOL Concerns of Patients With Hematologic Cancers
Lesko has comprehensively reviewed the QOL concerns of patients with hematologic malignancies, including issues common to the cancer experience and those specific to leukemia and lymphoma. Due to the potential fatality of the disease and prolonged, complicated treatment approaches, these patients have heightened concern about issues of death, dependence, disfigurement, disruption, and disability. Other significant concerns related to living with uncertainty and the “emotional exhaustion” due to the potential long-term clinical course of the disease, financial burden, increased risk for depressive mood and anxiety, and family disruption.
Long-term survival issues included conditioned nausea and vomiting, medical concerns (long-term and late effects of treatment), and psychological concerns, such as fear of recurrence and abandoning the role of patient. Conditioned nausea and vomiting, for example, have been shown to extend 7 to 12 years beyond treatment in patients with Hodgkin’s disease.
Anxiety and Depression-Other research has demonstrated the prevalence of depression and anxiety in mixed lymphoma patients.[70-72] In one study of the prevalence of psychological distress in 2,388 patients with various types of cancer (breast, lung, colon, head and neck, gynecologic, prostate, and brain cancers, lymphoma, hepatoma), lymphoma patients scored highest for depression.
A high level of anxiety and depressive symptoms or illness (49%) was also found in a group of 98 patients with Hodgkin’s disease or NHL. Mood disturbance was associated with negative treatment effects (particularly pain and changes in appetite and taste). Common adverse effects of treatment included hair loss, vomiting, nausea, and loss of appetite. Quality-of-life effects of treatment-related emesis impaired the ability of some patients to complete tasks, work, care for themselves, perform normal daily activities, and enjoy social activities and meals. Following treatment, a subgroup of patients continued to experience a lack of energy, loss of libido, irritability, tiredness, and thinking/memory handicaps. Impairments in social adaptation were less well-defined, although patients reported problems or long-term delays in returning to work.
Symptoms of depression and anxiety over the impact of disease on health and life expectancy predominated in 40 mixed lymphoma patients. Psychological status did not change significantly over the course of early treatment, although other evidence has suggested that psychological symptoms at diagnosis are more severe than at 4 months post-diagnosis. Psychological adaptation in patients with chronic illness may be pivotal to coping with the physical, emotional, social, and functional disrup-tions caused by cancer, including lymphoma.[74,75]
Uncertainty about the illness- has been cited as a psychosocial issue in patients with hematologic malignancies. Unfortunately, available data relate to other diseases. One study of women with gynecologic cancers suggests that uncertainty about the illness-wellness state is predictive of some health-related QOL scores. Low-grade lymphoma patients may be at high risk for the negative implications of uncertainty, and may benefit from research evaluating the impact of uncertainty in illness, as well the value of implementing interventions designed to help patients cope with uncertainty and fear of recurrence or progression.
In a group of 40 mixed cancer patients (including lymphoma patients), the negative impact of cancer recurrence has been shown to be considerable, often distinguished as being more traumatic than the initial diagnosis. Risk of emotional trauma at points of recurrence are likely to be substantial in patients with low-grade lymphoma. Loss of control (physical and psychologically based), feelings of grief and anger, presence of chronic fatigue, and other long-term and late effects (such as permanent central nervous system damage and infertility), altered self-esteem and self-image, difficulties with resumption of prediagnosis roles, somatic fixation at disease-free intervals, employment and insurance discrimination, and family disruption have also been addressed,[16,76,79-81] but deserve further attention. Table 1 lists the major QOL issues that may concern patients with low-grade lymphoma.
Positive Adaptation to Illness-Low-grade lymphoma patients may suffer diverse treatment and psychosocial consequences, with a select group able to live a relatively healthy and active lifestyle for a considerable time following diagnosis. Some patients will be exposed to aggressive and experimental therapies, while others, especially the elderly, may endure a less toxic, less debilitating course of treatment.
Psychosocial adaptation to illness and survival seem to be highly influenced by a host of variables and, therefore, are likely to vary from patient to patient. Positive aspects of living with chronic or terminal illness have been documented and should not be overlooked in this population. Social, family, and emotional domains have been shown to be positively influenced by life-threatening illness.[75,82] The ability to find meaning in illness, “dispositional optimism,” and hope are thought to mediate this effect. Patients may report an increased awareness and enjoyment of “life in the moment” or find value in such things as the coping skills developed by children who have lived with a parent who has a chronic illness or who have faced parental loss.
An understanding of the overall QOL of people with NHL can be achieved by combining the medical/physical aspects of the disease (described earlier) with its psychosocial sequelae. Taken together, the physical, functional, psychological, and social impact of NHL and its treatment can be evaluated using one of the currently available QOL questionnaires created for people living with cancer. One such questionnaire, the Functional Assessment of Cancer Therapy-General (FACT-G), has been administered in an ongoing study to over 1,000 cancer patients, many of whom have NHL. Some of these data will be presented below.
NHL Patients Compared to Other Cancer Patients
Table 2 presents QOL (FACT-G) data from a mixed sample of 141 patients (inpatients and outpatients) with NHL. These patients represent a subset of a larger sample of 1,196 patients with mixed cancers from five institutions (Rush-Presbyterian-St. Luke’s Medical Center, Northwestern University, Medical College of Ohio, Fox Chase Cancer Center, and Johns Hopkins Oncology Center). The mean FACT-G scores are quite comparable to those of the original standardization sample.
To allow a direct comparison of FACT subscale scores between NHL patients and patients with general solid tumors from the same study, an age- and gender-matched group of 141 general cancer patients was extracted. This comparison showed no significant differences on any of the FACT subscales, suggesting that the QOL of NHL patients is generally comparable to that of patients with other cancers.
To examine the comparability of patients with NHL to patients with other lymphomas (ie, Hodgkin’s disease), a subset of 32 NHL patients, again matched for age and gender to the existing set of 32 Hodgkin’s disease patients, was extracted. This comparison, unlike the previous one, showed that the NHL patients reported significantly lower physical and functional well-being than the Hodgkin’s disease patients (see Table 3). These lower scores resulted in decreased FACT-G (total QOL) scores as well.
To follow up on this difference, a multiple regression analysis was conducted on the matched groups, entering five predictors of FACT physical well-being and functional well-being scores: diagnosis; Eastern Cooperative Oncology Group (ECOG) performance status; stage of disease; current radiotherapy; and current chemotherapy. The purpose of this analysis was to help determine the extent to which each of these variables contributes to the decline in QOL seen among NHL patients (Table 4). For this reason, all of the factors were entered simultaneously using a stepwise approach, followed by relevant analysis of covariance to confirm unique explanatory ability where noted.
In the first (physical well-being) model, performance status and current chemotherapy were both strongly predictive of physical well-being score, with the five-variable model explaining 48% of its variance. Interestingly, diagnosis itself and stage of disease were not significant factors. Current radiotherapy may have been a nonfactor due to the very low number of patients currently receiving that mode of therapy (5 out of 64). In the second (functional well-being) model, only diagnosis (Hodgkin’s disease vs NHL) was predictive of functional well-being score, and the predictive ability was weak overall, explaining only 17% of its variance.
The wording of items in each of the subscales (Table 5) may shed some light on why physical well-being scores were so much more responsive to the effects of chemotherapy. First, all of the items in the physical well-being questionnaire are negatively worded, reflecting the perceived physical state. In contrast, the functional well-being questions are positively worded and emphasize functional ability, which may be less directly and less strongly compromised compared to physical symptoms. A second possible reason is that the physical well-being subscale specifically asks about treatment side effects.
In any event, it is clear from Table 4 not only that physical well-being is very strongly related to performance status but also that, independent of this
relationship, the physical well-being component of QOL is worsened by chemotherapy. This appears to be a more salient factor than age, gender, or actual type of lymphoma (Hodgkin’s disease vs NHL).
NHL Patients Who Did and Did Not Receive Chemotherapy
This observation led us back to our original complete set of 141 NHL patients, which we divided into those who received chemotherapy vs those did not (Table 6). A comparison of these two groups showed that patients receiving chemotherapy showed significantly lower physical, emotional, and functional well-being, as well as lower total QOL scores. These differences, presented in Table 6 as unadjusted mean differences for the sake of easy comparison to other samples of patients, remained statistically significant after adjustments were made for other covariates (age, gender, performance status, and stage of disease).
These data provide some empirical support for something that is obvious to most clinicians; namely, that in the absence of a possible direct benefit on disease symptoms, chemotherapy is detrimental to short-term QOL. More importantly, these data provide a basis for comparison to other patient groups, and evidence that the QOL metric produced by the FACT can produce useful, responsive scores in this population. This is not to say that a lymphoma-specific subscale would not be a useful complement to the FACT-G, particularly for the purpose of obtaining lymphoma-specific information related to B symptoms, unique treatment concerns, and strategies for coping with a chronic disease. Such a subscale probably would add a dimension of sensitivity to the assessment.
Comparison of Two Groups Receiving Chemotherapy
As an illustration of how these data, as described, can be used in comparisons with other patient samples, we drew data from a different study of mixed cancer patients (227 of whom had NHL and 46, Hodgkin’s disease; sample 2 in Table 7). The purpose of this analysis was not to make a direct statistical comparison between the groups, but rather, to present scores side-by-side to allow rough comparisons to be made. This sample of patients was drawn from a community phase IV trial of epoetin alfa (Epogen, Procrit) for the treatment of anemia related to chemotherapy. All of these patients were, therefore, receiving chemotherapy and had hemoglobin levels below 11 g/dL. Thus, the group of 80 NHL patients receiving chemotherapy from Table 6 would provide a useful comparison (sample 1 in Table 7).
Visual comparison of the NHL patients in sample 1 and sample 2 reveals strikingly similar unadjusted mean scores. On the other hand, the sample 2 NHL patients appear to have higher QOL than the sample 2 Hodgkin’s disease patients, in contrast to the sample 1 data presented earlier. However, these differences are not significant after the effects of age and gender are removed.
It has commonly been observed that, under conditions of similar objective health data, older patients tend to report better emotional and even physical well-being. This highlights the importance of considering nondisease factors when comparing QOL data across samples. It is not at all unusual to find that, although different diseases have very unique natural histories, symptoms, and treatment considerations, the QOL considerations and differences may be more strongly related to such factors as age and whether or not the patient is currently receiving treatment.
Taken as a whole, the data presented here support a long-held clinical notion about NHL: Given the questionable survival benefit of most treatment options, and given the known adverse impact of chemotherapy on QOL, it seems prudent to manage patients with less aggressive approaches when possible. The presence or absence of disease symptoms is often the determining factor when deciding about treatment, with treatment more likely when symptoms are present. It appears reasonable to conclude that the adverse effects of toxic treatments (ie, cytotoxic chemotherapy) are not easily offset by improvements in clinical outcome or the emotional advantages of receiving treatment, although this conclusion is based on observational data in uncontrolled clinical settings. Therefore, a watch-and-wait or minimally toxic approach to the managements of some patients with low-grade NHL seems to be well-justified. Of course, patient values and preferences for aggressive therapy must be factored into this general equation.
1. Parker SL, Tong T, Bolden S, et al: Cancer statistics, 1997. CA Cancer J Clin 47(1):5-27, 1997.
2. Aviles A, Talavera A, Guzman R, et al: Treatment of refractory low-grade lymphoma with chlorambucil alternating with interferon and radiotherapy. Cancer Biother 10(4):273-277, 1995.
3. Molina A, Pezner RD: Non-Hodgkin’s lymphoma, in Pazdur R, Coia LR, Hoskins WJ, et al (eds): Cancer Management: A Multidisciplinary Approach, 2nd ed, pp 239-269. Huntington, New York, PRR, 1997.
4. Weisdorf DJ, Anderson JW, Glick JH, et al: Survival after relapse of low-grade non-Hodgkin’s lymphoma: Implications for marrow transplantation. J Clin Oncol 10(6):942-947, 1992.
5. Hardy R, Horning SJ: Lymphomas: non-Hodgkin’s, in Dollinger M, Rosenbaum E, Cable G (eds): Everyone’s Guide to Cancer Therapy, 2nd ed (revised), pp 492-500. Kansas City, Andrews & McMeel, 1994.
6. Stein R: A Chemotherapy of human cancer: Hodgkin’s disease and malignant lymphomas, in Skeel RT, Lachant NA (eds): Handbook of Cancer Chemotherapy, 4th ed, pp 450-483. Boston, Little Brown, 1995.
7. Hagemeister FB: Low grade lymphomas: New entities and treatment concepts. Med Oncol 12(3):131-142, 1995.
8. Rosenberg SA: The low-grade non-Hodgkin’s lymphomas: Challenges and opportunities. J Clin Oncol 3(3):299-310, 1985.
9. Vose JM: Classification and clinical course of low-grade non-Hodgkin’s lymphomas with overview of therapy. Ann Oncol 7(suppl):S13-19, 1996.
10. Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment of Cancer Therapy (FACT) scale: Development and validation of the general measure. J Clin Oncol 11(3):570-579, 1993.
11. Ware JE, Sherbourne CD: The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual framework and item selection. Med Care 30(6):473-483, 1992.
12. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85(5):365-376, 1993.
13. Rosenberg S, Berard C, Brown J, et al: National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage: The non-Hodgkin’s lymphoma Pathologic Classification Project. Cancer 49:2112, 1982.
14. Harris NL, Jaffee ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84(5):1361-1392, 1994.
15. Carbone PP, Kaplan HS, Musshoff K, et al: Report on the committee on Hodgkin’s disease staging classification. Cancer Res 31:1860-1861, 1971.
16. Lesko L: Hematological malignancies, in Holland HC, Rowland JH (eds): Handbook of Psychooncology: Psychological care of the patient with cancer, pp 218-231. New York, Oxford University Press, 1989.
17. Horning SJ, Rosenberg SA: The natural history of initially untreated low-grade non-Hodgkin’s lymphomas. N Engl J Med 311(23):1471-1475, 1984.
18. Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4(10):1470-1480, 1986.
19. Maksymiuk AW, Haines C, Tan LK, et al: Age-related prognostic factor analyis in non-Hodgkin’s lymphoma. Can J Oncol 6(1):435-442, 1996.
20. Lopez-Guillermo A, Montserrat E, Bosch F, et al: Low-grade lymphoma: Clinical and prognostic studies in a series of 143 patients from a single institution. Leuk Lymphoma 15:159-165, 1994.
21. Morel P, Dupriez B, Plantier-Colcher I, et al: Long term outcome of follicular low-grade lymphoma: A report of 91 patients. Ann Hematol 66(6):303-308, 1993.
22. Parker D, Alison DL, Barnard DL, et al: Prognosis in low-grade non-Hodgkin’s lymphoma: Relevance of the number of sites involved, absolute lymphocyte count and serum immunoglobulin level. Hematol Oncol 12:15-27, 1994.
23. Lichtman SM: Lymphoma in the older patient. Semin Oncol 22(1;suppl1):25-28, 1995.
24. Armitage JO: Treatment of non-Hodgkin’s lymphoma. N Engl J Med 328(14):1023-1030, 1993.
25. Yuen AR, Kamel OW, Halpern J, et al: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13(7):1726-1733, 1995.
26. Travis LB, Curtis RE, Glimelius B, et al: Second cancers among long-term survivors of non-Hodgkin’s lymphoma. J Natl Cancer Inst 85(23):1932-1937, 1993.
27. MacManus MP, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14(4):1282-1290, 1996.
28. Kimby E , Mellstedt H: Chlorambucil/prednisone (ChP) vs CHOP in symptomatic low-grade lymphomas. Fifth International Conference on Malignant Lymphoma, p 53. Lugano, Switzerland, June 9-12, 1993.
29. Dana BW, Dahlberg S, Nathwani BN, et al: Long-term follow-up of patients with low-grade lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherpay. J Clin Oncol 11(4):644-651, 1993.
30. Hoppe RT, Kushlan P, Kaplan HS, et al: The treatment of advanced stage favorable histology non-Hodgkin’s lymphoma: A preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood 58(3):592-598, 1981.
31. Cole B: Clinical benefits vs quality of life of patients receiving interferon. OncoLink Home Page, May 22, 1996. http://oncolink, upenn.edu
32. National Cancer Institute: Radiation and. You: A Guide To Self-Help During Treatment. NIH Publication no. 95-2227. Bethesda, Maryland, National Cancer Institute, revised October 1993.
33. Chatterjee R, Goldstone AH: Gonadal damage and effects of fertility in adult patients with hematological malignancy undergoing stem cell transplantation. Bone Marrow Transplant 17:5-11, 1996.
34. Mendelson D, Block J, Serpick A: Effect of large intermittent intravenous doses of cyclophosphamide in lymphoma. Cancer 25(3):715-720, 1970.
35. Kaung D, Wittington R, Spencer H, et al: Comparison of chlorambucil and streptonigrin (NSC-45393) in the treatment of malignant lymphomas. Cancer 23(6):1280-1283, 1969.
36. Rijlaarsdam J, Toonstra J, Meijer O, et al: Treatment of primary B-cell lymphomas of follicle center cell origin: A clinical follow-up of 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol 14(2):549-555, 1996.
37. Fisher R, Gaynor E, Dahlberg S, et al: Comparison of standard regimen CHOP with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328(14):1002-1006, 1993.
38. Jones SE, Grozea PN, Miller TP, et al: Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone alone or with levamisole or with levamisole plus BCG for malignant lymphoma: A Southwest Oncology Group study. J Clin Oncol 3(10):1318-1324, 1985.
39. Meyer R, Browman G, Samosh M, et al: Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma. J Clin Oncol 13(9):2386-2393, 1995.
40. Pryzant RM, Meistrich ML, Wilson G, et al: Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin’s lymphomas. J Clin Oncol 11(2):239-247, 1993.
41. Rybak ME, Anderson J, Kaplan R, et al: A phase II trial of etoposide and cisplatin in patients with refractory and relapsed non-Hodgkin’s lymphoma: Cancer and Leukemia Group B study 8351. Med Pediatr Oncol 21:441-445, 1993.
42. McLaughlin P, Hagemeister FB, Romaguera JE, et al: Fludarabine, mitoxantrone, and dexamethasone: An effective new regimen for indolent lymphoma. J Clin Oncol (4):1262-1268, 1996.
43. Velasquez WS, Cabanillas F, Salvador P, et al: Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood 71(1):117-122, 1988.
44. Pott-Hoeck C, Hiddemann W: Purine analogs in the treatment of low-grade lymphomas and chronic lymphocytic leukemia. Ann Oncol 6(5):421-433, 1995.
45. Piro LD: Cladribine in the treatment of low-grade NHL. Semin Hematol 33(1;suppl):34-39, 1996.
46. Morton J, Taylor K, Bunce I, et al: High response rates with short infusional 2-chlorodeoxyadenosine in de novo and relapsed low-grade lymphoma: Australian and New Zealand Study Group. Br J Haematol 95:110-115, 1996.
47. Hochster HS, Kim K, Green MD, et al: Activity of fludarabine in previously treated non-Hodgkin’s low-grade lymphoma: Results of an Eastern Cooperative Oncology Group study. J Clin Oncol 10(1):28-32, 1992.
48. Rohatiner A, Foran J, Coiffier B, et al: Fludarabine in newly-diagnosed diffuse low-grade non-Hodgkin’s lymphoma (abstract 1287). Proc Am Soc Clin Oncol 15:419, 1996.
49. Hoffman MA: Cladribine for the treatment of indolent non-Hodgkin’s lymphoma. Semin Hematol 33(1;suppl 1):40-44, 1996.
50. Szelenyi H, Foss HD, Kreuser ED, et al: Fatal mucor pneumonia after treatment with 2-chlorodeoxyadenosine for non-Hodgkin’s lymphoma. Ann Hematol 73(3):145-147, 1996.
51. Betticher DC, von Rohr A, Ratschiller D, et al: Fewer infections, but maintained anti-tumor activity with moderate vs standard dose cladribine (2-CDA) in pretreated patients with low grade non-Hodgkin’s lymphoma (NHL) (abstract 56). Proc Am Soc Clin Oncol 16:16a, 1997.
52. Freedman AS, Gribben JG, Neuberg D, et al: High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood 88(7):2780-2786, 1996.
53. Shouten IC, Raemaekers JJ, Kluin-Nelemans HC, et al: High dose therapy followed by bone marrow transplantation for relapsed follicular non-Hodgkin’s lymphoma: Dutch HOVON Group. Ann Hematol 73(6):273-277, 1996.
54. Suki S, McLaughlin P, Przepiorka D, et al: The role of bone marrow transplantation (BMT) in 39 adult patients with low-grade non-Hodgkin’s lymphoma (NHL) (abstract 1288). Proc Am Soc Clin Oncol 12:378, 1993.
55. Lazarus HM: Bone marrow transplantation in low-grade non-Hodgkin’s lymphoma. Leuk Lymphoma 17:199-210, 1995.
56. Bierman PJ, Vose JM, Anderson JR, et al: High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin’s lymphoma. J Clin Oncol 15(2):445-450, 1997.
57. Syrjala KL, Chapko MK, Vitaliano PP, et al: Recovery after allogeneic marrow transplantation: Prospective study of predictors of long-term physical and psychosocial functioning. Bone Marrow Transplant 11:319-327, 1993.
58. Andrykowski MA, Greiner CB, Altmaler EM, et al: Quality of life following bone marrow transplantation: Findings from a multicentre study. Br J Cancer 71(6):1322-1329, 1995.
59. Davis TA, Maloney DG, Liles TM, et al: Long-term remissions in patients treated with anti-idiotype monoclonal antibodies for non-Hodgkin’s lymphoma (abstract 1383). Proc Am Soc Clin Oncol 15:444, 1996.
60. McLaughlin P, Grillo-LÃ³pez AJ, Czuczman M, et al: IDEC-C2B8 (rituximab): Clinical activity in clinically chemoresistant (CCRD) low-grade or follicular lymphoma (LG/F NHL) and in patients relapsing after anthracycline therapy (Anthra-Rx) or ABMT (abstract 55). Proc Am Soc Clin Oncol 16:16a, 1997.
61. Tang SC, Hewitt HK, Bernstein NL: Objective clinical response in patients with recurrent low-grade lymphoma treated with CAMPATH-1H monoclonal antibody (abstract 1255). Proc Am Soc Clin Oncol 14:399, 1995.
62. Ezdinli EZ, Harrington DP, Kucuk O, et al: The effect of intensive intermittent maintenance therapy in advanced low-grade non-Hodgkin’s lymphoma. Cancer 60(2):156-160, 1987.
63. Hagenbeek A, Carde P, Somers R, et al: Interferon-alfa-2a versus control as maintenance therapy for low-grade non-Hodgkin’s lymphoma: Results from a prospective randomized clinical trial (abstract 1203). Proc Am Soc Clin Oncol 14:386, 1995.
64. Ludwig H, Fritz E, Neuda J, et al: Which risk/benefit tradeoffs would lead patients with myeloma to opt for interferon treatment? (abstract 40). Proc Am Soc Clin Oncol 16:12a, 1997.
65. McLaughlin P, Cabanillas F, Hagemeister FB, et al: CHOP-Bleo plus interferon for stage IV low-grade lymphoma. Ann Oncol 4(3):205-222, 1993.
66. Henry-Amar M: Hodgkin’s disease: Treatment sequelae and quality of life. Baillieres Clinical Hematol 9(3):595-618, 1996.
67. Kornblith AB, Anderson J, Cella DF, et al: Hodgkin’s disease survivors at increased risk for problems in psychosocial adaptation. Cancer 70(8):2214-2224, 1992.
68. Cella D, Fairclough DL, Bonomi PB, et al: Quality of life (QOL) in advanced non-small cell lung cancer (NSCLC): Results from Eastern Cooperative Oncology Group (ECOG) study E5592 (abstract 4). Proc Am Soc Clin Oncol 16:2a, 1997.
69. Cella DF, Pratt A, Holland JC: Persistent anticipatory nausea, vomiting, and anxiety in cured Hodgkin’s disease patients after completion of chemotherapy. Am J Psychiatry 143:641-643, 1986.
70. Zabora JR, Brintzenhofcszoc KM, Smith ED: Prevalence of psychological distress by cancer site (abstract 1627). Proc Am Soc Clin Oncol 15:507, 1996.
71. Pettingale KW, Burgess C, Greer S: Psychological response to cancer diagnosis: I. Correlations with prognostic variables. J Psychosom Res 32(3):255-261, 1988.
72. Devlen J, Maguire P, Phillips P, et al: Psychological problems associated with diagnosis and treatment of lymphoma: I. Retrospective study. Br Med J 295:953-954, 1987.
73. Lloyd GG, Parker AC, Ludlam CA, et al: Emotional impact of diagnosis and early treatment of lymphomas. J Psychosom Res 28(2):157-162, 1984.
74. Cassileth BR, Lusk EJ, Strouse TB, et al: Psychosocial status in chronic illness: A comparative analysis of 6 diagnostic groups. N Engl J Med 311:506-511, 1984.
75. Taylor EJ: Whys and wherefores: Adult patient perspectives of the meaning of cancer. Semin Oncol Nurs 11:32-40, 1995.
76. Persson L, Hallberg IR: Acute leukemia and malignant lymphoma patients experience of disease, treatment, and nursing care during the active treatment phase: An explorative study. Eur J Cancer Care 4(3):133-142, 1995.
77. Padilla GV, Mishel MH, Grant MM: Uncertainty, appraisal and quality of life. Qual Life Res 1(3):155-165, 1992.
78. Cella DF, Mahon SM, Donovan, MI: Cancer recurrence as a traumatic event. Behav Med 16(1):15-22, 1990.
79. Harpham WS: After Cancer: A Guide to Your New Life. New York, WW Norton, 1994.
80. Wallwork L, Richardson A: Beyond cancer: Changes, problems and needs expressed by adult lymphoma survivors attending an out-patients clinic. Eur J Cancer Care 3(3):122-132, 1994.
81. Zittoun R: Quality of life in hematological malignancies with brief reference to bone marrow transplantation (editorial). Leuk Res 17(9):727-731, 1993.
82. Curbow B, Somerfield MR, Baker F, et al: Personal changes, dispositional optimism, and psychological adjustment to bone marrow transplant. J Behav Med 16:423-442, 1993.
83. Brody J: Children need special help when a parent has cancer. The New York Times Health, Wednesday, February 12, 1997.