Assessment of quality of life during chemotherapy.

Increasingly more aggressive chemotherapy together with expected small differences between treatments with respect to objective endpoints has heightened awareness about the importance of addressing how patients experience and value the impact that treatment has had on their overall life situation. Assessment of a patient's quality of life (QoL) is now conceptually viewed as an important complement to traditional objective evaluation measures. It was therefore considered important to review the basis for the assessment of this endpoint when The Swedish Council of Technology Assessment in Health Care (SBU) performed a systematic overview of chemotherapy effects in several tumour types. The group came to the following conclusions: QoL assessments, mostly by patient self-reporting in questionnaires, have come increasingly into use during the past decade. A number of general, cancer-specific and cancer diagnosis-specific instruments have been developed. There is at present little need for development of new cancer instruments, although specific treatment modalities and tumour types may need new additional modules. A predefined hypothesis should determine the instrument to be used. Since the selection of a QoL instrument in a specific study influences both the results and the conclusions, it is essential to carefully select the instrument or instruments that have the greatest likelihood of identifying relevant differences between treatment alternatives. Interpretation of QoL data is more difficult than interpretation of objective endpoints such as survival time, objective response rates or toxicity. Despite these difficulties, QoL analyses have provided new insights into the advantages and disadvantages of various treatments not provided by traditional end-points. Some palliative treatments seemingly increase patients' QoL despite side-effects or the lack of, or marginal, increases in survival. When using potentially curative chemotherapy, it is not a matter of when the treatment should be started, but rather when it should be concluded. When using less active chemotherapy, the expected small therapeutic gains must be weighed against the QoL costs of using the therapy: does the toxicity and/or the inconvenience of the proposed treatment justify the expected gain? When it is found that the strain on the patient is greater than the effects of the cancer, treatment must be discontinued. It is not possible to determine whether or not the advantages of palliative chemotherapy are worth their costs without knowledge about patients' personal values regarding the influence on factors of relevance for QoL. The mostly used QoL questionnaires do not consider individual preferences, which therefore need to be addressed in the dialogue with the patient. QoL assessment is clearly in need of further methodological improvement before this endpoint can be regarded as fully established with respect to ability to provide unequivocally useful data in clinical trials. The multitude of questionnaires, missing data, lack of pre-study hypotheses of relevant differences between treatments and data multiplicity giving a risk for chance findings are examples of serious methodological problems. Patient response-shifts over time further complicate the interpretation of the data. Thus, QoL data, also from seemingly well-performed clinical trials, have to be interpreted cautiously. The international development during recent years has aimed at creating increased standardization of QoL measures. This has created greater possibilities to compare results from different trials. Hopefully, this also implies that it will be possible to draw firmer conclusions from QoL measurements in recently completed or ongoing trials than has been the case previously. QoL assessments are resource demanding even when short standardized questionnaires are used. Since cancer patients also generally give priority to anticancer effects over toxicity and convenience, QoL assessments in clinical trials are motivated mainly in study settings comparing treatments without expected major differences of outcome in objective endpoints.     

Treatment of recurrent metastatic medulloblastoma with intensive chemotherapy and allogeneic bone marrow transplantation

We report here the first known case of a patient with recurrent metastatic medulloblastoma to achieve long-term disease-free survival following treatment with allogeneic bone marrow transplantation. A 27 year old white male with recurrent metastatic medulloblastoma involving lymph nodes, bone and bone marrow was treated with multi-agent chemotherapy followed by allogeneic bone marrow transplantation from an HLA-identical sibling donor. Morbidity was acceptable with moderate to severe mucositis in the immediate post transplant period and clinical grade I graft versus host disease of the skin controlled with modest doses of corticosteroids. The patient continues in unmaintained complete remission in excess of 28 months with a performance status of 100%. Allogeneic marrow transplantation following cytoreductive salvage chemotherapy is an aggressive strategy that may offer an improved likelihood of disease eradication and ultimate cure for poor prognosis patients with recurrent metastatic medulloblastoma.     

Physical exercise and quality of life in cancer patients following high dose chemotherapy and autologous bone marrow transplantation

Preliminary evidence indicates that physical exercise may be an effective strategy for the rehabilitation of cancer patients following high dose chemotherapy (HDC) and bone marrow transplantation (BMT), but the focus of this research has been on physical fitness and medical outcomes. In the present study, we employed a prospective design to examine the relationship between physical exercise and various quality of life (QOL) indices in 25 BMT patients. Participants completed weekly self-administered questionnaires upon being admitted to hospital, and monitored the frequency and duration of their exercise during hospitalization. Statistical analyses indicated that exercise during hospitalization was significantly correlated with almost all QOL indices, including physical well-being, psychological well-being, depression, anxiety and days hospitalized. Moreover, only some of the correlations were attenuated after controlling for relevant demographic and medical variables. It was concluded that physical exercise may be related to QOL in BMT patients, but that experimental research is needed before any definitive conclusions can be drawn.     

Do quality of life or physical function at diagnosis predict short-term outcomes during intensive chemotherapy in AML?

BackgroundIntensive chemotherapy (IC) used to treat acute myeloid leukemia (AML) is associated with toxicity, particularly in older adults. Emerging data suggest that baseline quality of life (QOL) and physical function may predict outcomes in oncology, although data in AML are limited. We investigated the association between baseline QOL and physical function with short-term treatment outcomes in adults and elderly AML patients.Materials and methodsWe conducted a prospective, longitudinal study of adults (age 18+) AML patients undergoing IC. Before starting IC, patients completed the European Organisation for the Research and Treatment of Cancer (EORTC) 30-item questionnaire (QLQ-C30) and Functional Assessment of Cancer Therapy Fatigue subscale (FACT-Fatigue) in addition to physical function tests (grip strength, timed chair stands, 2-min walk test). Outcomes included 60-day mortality, intensive care unit (ICU) admission and achievement of complete remission (CR). Logistic regression was carried out to evaluate each outcome.ResultsOf the 239 patients (median age 57.5 years), 56.7% were male and median Charlson comorbidity score was 0. Sixty-day mortality, ICU admission and CR occurred in 9 (3.7%), 15 (6.3%) and 167 (69.9%) patients, respectively. Using univariate regression, neither QOL nor physical function at presentation was predictive of 60-day mortality (all P > 0.05), whereas ICU admission (P < 0.001) and remission status at 30 days (P = 0.007) were. Fatigue (P = 0.004) and role functioning (P = 0.003) were predictors of ICU admission; QOL and physical function were not. A higher Charlson score predicted ICU admission (P = 0.01) and remission status (P = 0.002). The cytogenetic risk group was associated with achievement of CR (P = 0.02); QOL and physical function were not (all P > 0.05). Findings were similar when patients age 60+ were examined. Relationships between fatigue and role functioning with ICU admission deserve further exploration.ConclusionsBaseline QOL and physical function tests in this prospective study were not associated with short-term mortality, ICU admission or achievement of CR after the first cycle of chemotherapy.     

Testicular function following bone marrow transplantation performed during or after puberty

Testicular function was assessed in eight males who had undergone bone marrow transplantation (BMT) during or shortly after puberty. Their ages ranged between 10 years, 10 months and 17 years, 3 months (median, 13 years, 7 months) at the time of BMT, and they were followed 13 to 77 months (median, 36 months) posttransplantation. Therapy for BMT consisted of high-dose, short-term chemotherapy either alone (Group I) or in combination with single-dose irradiation, total lymphoid (Group II) or total body (Group III). Subjects in Group III had all received combination chemotherapy prior to BMT. Hormonal and clinical evidence of germ-cell dysfunction was common in that 6 patients manifested elevated plasma levels of follicle-stimulating hormone (FSH), and four subjects were found to have a subnormal testicular volume. Of the six patients with abnormal FSH values, four were followed serially, and all showed normalization over time. Leydig cell function was less impaired in that seven of the eight patients produced normal adult male levels of testosterone, including three subjects with elevated luteinizing hormone (LH) levels. All eight developed normal adult male secondary sexual characteristics. It is concluded that the therapy utilized for BMT causes damage primarily to germinal epithelium which appears amenable to recovery. This may be due, in part, to the use of single dose rather than fractionated radiation.     

Cognitive functioning and quality of life in long-term adult survivors of bone marrow transplantation

BACKGROUND: The late neurotoxic effects of bone marrow transplantation (BMT) on cognitive functioning and quality of life (QOL) were investigated in a consecutively treated cohort of long-term adult survivors. METHODS: Progression-free patients treated with BMT or peripheral stem cell grafts for a hematologic malignancy at least 2 years before study participation were examined with a comprehensive battery of neuropsychological tests and questionnaires for QOL and mood states. The results of the neuropsychological tests were compared with healthy population norms. RESULTS: Forty patients were included, 87.5% of whom had undergone an allogeneic transplantation. All received total body irradiation up to 12 Gy (in two fractions). Assessment took place 22-82 months after BMT. Mild to moderate cognitive impairment was found in 24 patients (60%). Compared with healthy population norms, selective attention and executive function, information processing speed, verbal learning, and verbal and visual memory were most likely to be affected. The mean score for the total patient group revealed that these patients scored significantly lower on the information processing speed task compared with expected scores obtained from the normal population. The main predictors for poor neuropsychological performance were fatigue, global health, and educational level. Other correlations with moderate to severe cognitive impairment were subjective cognitive complaints, physical functioning, social functioning, overall mood states, and employment status. CONCLUSIONS: These data indicate that BMT may lead to cognitive complaints and late cognitive deficits in long-term adult survivors. Cognitive functioning should therefore be used as an outcome parameter in BMT studies.     

Role of autologous bone marrow transplantation in cancer chemotherapy

Over the past 9 years, total number of 147 patients with various types of malignant solid tumors were treated 220 times with high-dose chemotherapy supported by autologous bone marrow transplantation. Two most frequently used chemotherapeutic protocols were: cyclophosphamide 1,600 mg/m2 + adriamycin 80 mg/m2 + ACNU 3 mg/kg and cyclophosphamide 1,600-2,400 mg/m2 + adriamycin 80 mg/m2 + CDDP 100-120 mg/m2. There were 89 patients with advanced and/or recurrent diseases. The overall response (CR + PR) rate was 44.1% with the complete response (CR) rate, being 11.8% among 68 evaluable patients in this group. The most favorable response was obtained in breast cancer patients with 77.3% response rate and 13.6% CR rate. Nearly 50% of patients with gastric, lung, gynecological and pediatric malignancies responded, whereas poor responses were observed in the cases of pancreato-biliary, colorectal, esophageal cancers and melanoma. In 8 complete responders, three are alive and well without any evidence of disease 5 years after the treatment. There were 58 patients who underwent this treatment in adjuvant settings. There are 5 patients with breast cancer who have been followed over 5 years after treatment. All of them are alive and well without any demonstrable diseases. Four of them were in stage IIIa and histologically examined axillary nodes were positive in 14/15, 11/17, 37/44, 22/25. Autologous bone marrow transplantation seems to be instrumental in shortening the period of myelosuppression, thus allowing safe dose escalation in chemotherapy. Adequacy of cryopreserved marrow as marrow inoculum was ascertained with mononuclear cell count, cellular viability, CFU-GM, CFU-E, BFU-E and CFU-Mk.     

High-dose chemotherapy without autologous bone marrow transplantation in melanoma

High-dose chemotherapy with BCNU, melphalan, or both, followed by autologous bone marrow transplantation (ABMT) has been reported to produce response rates in excess of 60% in patients with advanced melanoma. We tested doses of BCNU associated with reversible bone marrow toxicity and acceptable extramedullary toxicity without the use of ABMT in 19 patients with a diagnosis of advanced malignant melanoma. All patients were evaluable for toxicity and 18 were evaluable for response; one patient had a new primary tumor. The patient population had a median age of 44 years (range, 16 to 71) and a median Karnofsky performance status of 80 (range, 50 to 100). Ten were women and nine were men, all had visceral dominant disease, and none had received previous chemotherapy. Our purpose was to test the feasibility of treatment without ABMT, its toxicity and efficacy, and the possibility of administering sequential repeated courses of therapy. Vincristine was added to the regimen to potentially increase efficacy. Treatment consisted of BCNU (750 mg/m2) and vincristine (2 mg days 1 and 8). Six patients who recovered bone marrow function received melphalan (60 mg/m2) and vincristine (2 mg days 1 and 8). Twenty-two percent (95% confidence limits, 3% to 39%) of patients had remissions (all partial) and these were of short duration. Toxicity was substantial with 16% early lethality and 29% incidence of lethal drug-related complications. Two patients (11%) died toxic after a second course of BCNU. Our results suggest that there is no practical role for high-dose BCNU in the treatment of melanoma.     

Histomorphologic study of bone marrow in acute leukemia following chemotherapy and autologous bone marrow transplantation

Twenty-six patients with acute myeloid leukemia, acute lymphoid leukemia and chronic granulocytic leukemia in blast crisis were studied by means of multiple biopsies during a polychemotherapeutic or autologous bone marrow transplant protocol. Following chemotherapy, 3 main phases were observed: leukemic cellular depletion, stromal bone marrow reconstruction, and bone marrow hemopoietic restoration. Following intensive chemotherapy (in 2 patients after cyclophosphamide and total body irradiation) and autologous bone marrow transplantation, the 3 phases appeared to be shorter. A focal or diffuse increase in marrow fibrosis was a common finding in leukemia. An effective antileukemic therapy resulted in a decrease in fibrosis, whereas in some cases a further increase was a precocious sign of leukemia relapse.     

High-dose chemotherapy and non-frozen autologous bone marrow transplantation in relapsed advanced lymphomas or those resistant to conventional chemotherapy

Ten patients with advanced, diffuse Hodgkin's and non-Hodgkin's lymphomas responding poorly to the most widely employed primary chemotherapy regimens were treated with a high-dose chemotherapy (HDC) followed by rescue with non-frozen autologous bone marrow infusion (ABMT). Complete remission (CR) was obtained in seven of ten patients (70%) and partial remission in two. Hemopoietic recovery occurred in nine cases. These preliminary results appear to indicate that HDC and non-frozen ABMT may be successfully used in patients with resistant or relapsed lymphomas.     

Recovery of blood and bone marrow stem cells following intense chemotherapy and autologous bone marrow transplantation

Sixteen patients with advanced (stage III) malignant melanoma were treated with escalating doses of intravenous BCNU and melphalan starting at 400 and 35 mg/m2, respectively, and escalating to 1,000 and 110 mg/m2, respectively, combined with autologous marrow transplantation. The duration of granulocytopenia and time to granulocyte recovery was similar in all groups regardless of chemotherapy dose. Platelet recovery was delayed in patients receiving the highest doses of chemotherapy. This study showed that bone marrow colony-forming units in culture took as long as 6 months to recover. This was adequate to bring peripheral blood counts to normal but not to pretreatment levels. These studies indicate that autologous bone marrow transplantation is beneficial in enhancing short-term recovery, but may not be beneficial in the long-term hematopoietic recovery.     

Intensive chemotherapy and bone marrow transplantation for myelodysplastic syndromes.

In myelodysplastic syndromes (MDS), complete remission rates of acute myelogenous leukemia (AML)-type chemotherapeutic regimens vary widely, ranging from 15% in patients with myelodysplasia after previous cytotoxic therapy to 61% in patients with refractory anemia with an excess of blasts in transformation without previous exposure to leukemogenic chemicals. The duration of remission is usually short, and those that exceed 24 months are unusual. Results of treatment are identical in the different types of MDS. No sufficient data on aggressive therapy are available for refractory anemia and refractory anemia with ringed sideroblasts. Prognostically favorable subgroups of patients are defined by age (below 45 or 50 years), no prior history of cytotoxic drug exposure, and absence of cytogenetic aberrations, especially of chromosomes 5 and/or 7. In contrast to AML-type chemotherapy, allogeneic bone marrow transplantation following high-dose (radio) chemotherapy offers a significantly greater chance of cure with a long-term relapse-free survival rate of 30% to 60%.     

High-dose chemotherapy with bone marrow transplantation for advanced colorectal cancer

A chemotherapy regimen based on high doses of BCNU and mitomycin C with autologous bone marrow transplantation was used in 18 patients with advanced colorectal carcinoma. Haematological toxicity was manageable, with a short nadir for white blood cells and platelets. The response rate was 33%, with a prevalence in peritoneal lesions compared to liver or lung metastases. Extra-haematological toxicity appeared in 16% of cases: a case of veno-occlusive disease of the liver and two cases of lung impairment are discussed. Although the response rate obtained with the regimen was satisfactory, the more extensive use of high-dose chemotherapy followed by autologous bone marrow transplantation requires the identification of less toxic protocols.     

Quality of life in adult patients after bone marrow transplantation

Background Since culture, history, personal financial situation, and the health insurance system are strongly associated with quality of life (QOL) for patients undergoing continuing medical care, any investigation into this subject should be done within individual areas and countries. Patients and Methods We investigated QOL in adult survivors after bone marrow transplantation (BMT), by administering a mail-back questionnaire to outpatients seen at 8 hospitals, in association with Nagoya BMT groups. Results The respondents surveyed were aged 20 years and older at the time of this study, and were not in life-threatening relapse. The underlying diseases were chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, malignant lymphoma, severe aplastic anemia, and myelodysplastic syndrome. The average age at the time of study was 37.6 years, and the median interval between transplantation and the time of study was 38.2 months. Eighty-four patients were treated with allogeneic BMT, 4 with autologous transplants, and 1 with a syngeneic transplant. Conclusion Our data showed that QOL gradually continued to improve over time, even 5 years after transplantation. We found that the older a patient was at the time of BMT or at the time he or she responded to the questionnaire, the poorer his or her QOL was. Total body irradiation as a part of preconditioning, a diagnosis of acute graft-versus-host disease (GVHD), and underlying disease were unrelated to QOL. Longer length of time since transplantation positively affects QOL, while diagnosis of chronic GVHD negatively affects QOL. Being of female sex and being of greater age were factors associated with a greater risk of job loss.     

High-dose chemotherapy and unpurged autologous bone marrow transplantation for acute leukemia in second or subsequent remission

The authors administered high-dose chemotherapy with cyclophosphamide, BCNU (carmustine) and VP-16 (etoposide) plus autologous bone marrow transplantation (ABMT) to 22 adult patients with relapsed acute leukemia in second or subsequent remission. The marrow was not treated ex vivo. The long-term, disease-free survival rate was 14%. Comparison of results with other treatments can be difficult because of patient selection biases. The concept of inversion (achievement of a longer remission with salvage therapy than with prior treatments) is proposed to compare treatment results. Three patients remain in complete remission beyond 4 years, with inversions. More intensive cytoreductive regimens will be needed to improve results.     

Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation

Background: The role of intensive chemotherapy with autologous blood andmarrow transplantation (ABMT) for patients with relapsed or refractoryintermediate grade non-Hodgkins lymphoma has recently been established.However, conventional dose salvage chemotherapy is frequently used todetermine chemotherapy sensitivity and reduce tumor bulk prior to intensivetherapy. Different salvage regimens have been proposed but none appearssignificantly superior. The purpose of this study was to determine theefficacy of mini-BEAM salvage chemotherapy in patients referred for ABMT andto define prognostic factors of response.Patients and methods: One hundred four patients referred forconsideration of ABMT after failure of primary anthracycline-basedchemotherapy received BCNU 60 mg/m² day 1, etoposide 75mg/m² day 2–5, ara-C 100 mg/m² q12h day2–5, melphalan 30 mg/m² day 6 (mini-BEAM) until maximumtumor reduction. Median age was 52 (range 18–65); 57% had failedto achieve a complete response (CR) to doxorubicin-based chemotherapy atdiagnosis and only 13% had a previous CR lasting > 12 months.Seventy-six received mini-BEAM as first salvage chemotherapy.Results: The overall response rate (RR) was 37% (95%confidence interval (CI) 28–46%) with 12 patients achieving CRand 25 achieving PR. Theresponse rate among patients treated as first salvage was 43% comparedto 20% for patients who had failed to respond to a previous salvageregimen. Only 15% of patients who failed to respond to mini-BEAMresponded to another conventional dose salvage regimen. Thirty-eight of 104patients ultimately demonstrated sufficient response to proceed to ABMT.Actuarial survival at four years is 22% for all 104 patients, and36% for those who went on to ABMT. For those who were not transplanted,four-year survival was 18%. B symptoms and tumor burden at relapse weresignificant predictors of response to mini-BEAM in multivariate analysis, andidentified a poor prognosis group of patients unlikely to be cured by thisapproach.Conclusions: Mini-BEAM does not appear to be a superior salvage regimen inthis high-risk group of relapsed or refractory NHL patients for whom ABMT wasthe ultimate treatment intention. Only one-third of patients referred for ABMTultimately proceed to transplant; alternative treatment strategies should bedeveloped for those with a low likelihood of cure by this approach.     

Phase II study of intensive chemotherapy with autologous bone marrow transplantation in patients in complete remission of disseminated breast cancer

SummaryBackground This trial studied the disease-free survival after high-dose chemotherapy in patients in complete remission of metastatic breast cancer.Patients and methods Thirty women, mean age 42.2 years (range 33–55) with metastatic breast cancer, received high-dose chemotherapy in a phase II study. Patients were eligible if they were 55 years of age, had achieved complete remission within 6 months of the initiation of chemotherapy, and had a WHO performance scale of 0 or 1. The high-dose regimen consisted of melphalan 180 mg/m² and mitoxantrone 60 mg/m² both divided over 3 days. On day 7 bone marrow and/or peripheral stem cells were infused. After bone marrow recovery, external beam radiation was administered to sites of previous metastatic disease in 15 patients.Results Apart from leuko- and thrombocytopenia, mucositis was the major side effect. One patient died during the bone marrow transplant period due to an aspergillus infection. The median follow-up since highdose chemotherapy is 25 months (range 13 to 56 months). The median disease-free survival since high-dose chemotherapy is 27 months and the disease free survival is still 43% with an overall survival of 53% at 3 years. In two patients tumor relapse occurred only in the brain; in one patient the only relapse sign was a meningeal carcinosis. At the moment 17 patients are disease-free (13+–56+) months after high-dose chemotherapy.Conclusion Until now this high-dose regimen in selected patients with complete remission after induction chemotherapy for metastatic breast cancer has a promising disease free survival.     

Allogeneic bone marrow transplantation for acute leukemia refractory to induction chemotherapy

This article compares the outcome of 14 patients with primary refractory acute leukemia who underwent bone marrow transplantation from human leukocyte antigen (HLA)-identical donors with that of 18 age-matched control patients who received chemotherapy. Complete clearing of leukemia was seen in all 14 transplanted patients. Five of the transplanted patients are alive 98 to 1790 days posttransplant, and four are free of leukemia. Nine patients have died, eight with severe graft-versus-host disease associated with interstitial pneumonia or systemic infections and one with relapse from chemotherapy-associated infections. Engraftment was seen in all patients. Severe graft-versus-host disease (grades III and IV) was seen in ten patients and resolved in three patients following high-dose corticosteroid treatment. Three of the 18 control patients are alive, none of them in complete remission. It appears that the combination of piperazinedione and total-body irradiation followed by allogeneic transplant is effective induction treatment for primary refractory acute leukemia and will be considered in the future as first salvage treatment for patients failing induction treatment.     

Intensive chemotherapy with autologous bone marrow transplantation for small-cell lung cancer

Summary Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160–200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800–1,200 mg/m² etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400–600 mg/m²), etoposide (120 mg/ m²x4) and either high-dose cyclophosphamide (40 mg/kg x4) or melphalan (140 mg/m²). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.This work was supported by the Cancer Research Campaign