Induction Phase Of Chemotherapy Research Articles

L‐asparaginase as a marker of chemotherapy dose modification in children with acute lymphoblastic leukemia

The objective of the current study was to compare chemotherapy dose modifications in obese (a body mass index [BMI] > 95%) and nonobese (a BMI < or = 95%) pediatric patients with acute lymphoblastic leukemia (ALL). The study cohort was comprised of 199 pediatric patients diagnosed with ALL who were treated at 1 of 2 South Texas pediatric oncology centers between 1990-2000. The relative chemotherapy dose modification during the induction phase of chemotherapy was calculated as the ratio of 1) the actual administered dose of L-asparaginase and 2) the protocol-calculated dose of L-asparaginase. The extent to which the chemotherapy dose modification varied according to obesity status was assessed using stratified Student t tests and an ordinary least-squares regression analysis. Obese ALL patients were found to exhibit a 7% decrease in the mean relative modification of L-asparaginase during induction chemotherapy compared with their nonobese counterparts. This finding was statistically significant (P = 0.009), even after adjustment for gender, age, ethnicity, and clinical institution. To the authors' knowledge, the current study is the first published report of an obesity-associated chemotherapy dose modification in pediatric patients with ALL, the most common childhood malignancy. It will be important to examine whether these findings are consistent with those observed in future studies, and ultimately to assess the association between obesity-related dose modifications and long-term cancer outcomes.

Oral treatment with yolk antibodies for the prevention of C. albicans infections in chemotherapy treated children. A feasibility study

Cancer patients treated with chemotherapy often become neutropenic, which predisposes for oral and systemic C. albicans infections. The purpose of this feasibility study was to find out if gargling with anti-C. albicans immunoglobulin Y from egg yolk can prevent oral candidiasis in children, treated for acute lymphatic leukemia. Four patients gargled with the antibodies once a day during the induction phase of chemotherapy. None of four patients treated with IgY got any C. albicans infection. In the non-treated control and in a historic group, seven of thirteen patients had suspected C. albicans infection. This study indicates that anti-C. albicans IgY may prevent oral candidiasis in immunocompromized children.

Early Allogeneic Hematopoietic Cell Transplantation during Induction Chemotherapy in High-Risk Acute Myeloid Leukemia.

Objectives: In patients with acute myeloid leukemia and high-risk cytogenetic aberrations or minor response to the first cycle of induction chemotherapy (IC) the probability of achieving a sustained complete remission is low. Thus early treatment intensification may be warranted in order to achieve long-term disease control. We performed a prospective trial to evaluate whether reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation (HSCT) from related or unrelated donors can be performed during the aplastic phase of IC in patients with poor-risk AML. Methods: Seventeen patients (n=17) aged between 17 and 63 years (median 45) with acute myeloid leukemia and high-risk cytogenetic aberrations (n=14, complex, inv3 or t(3;3), t(3;5), −7 or del 7q, +8) or more than 10 % marrow blasts on day 15 after the first cycle of IC (n=3) were included so far. During aplasia a median of thirteen days (range 7–35) after the first (n=8) or second (n=9) cycle of IC patients received 5 x 30 mg/m2 fludarabine i.v. combined with either 8 mg/kg busulfan p.o. (n=4) or 150 mg/m2 melphalan iv. (n=13) followed by allogeneic G-CSF mobilized peripheral blood stem cells (PBSC, n=16) or bone marrow (n=1) from related (n=7) or unrelated (n=10) donors. Nine out of seventeen patients were not in complete remission before conditioning therapy was started. Patients with unrelated grafts received antithymocyte globulin (4 x 10 mg/kg ATG Fresenius). GvHD prophylaxis was performed with cyclosporine A (CSP). Results: All patients engrafted (ANC &gt; 0.5 Gpt/l on day 11, range 8–19, platelets &gt; 50 Gpt/l day 15, range 11–32) and went into remission. Acute GvHD grade II-IV occurred in 8 patients and extensive chronic GvHD was documented in 5 patients with a follow-up of &gt; 100 days. Two patients died while being in remission from infectious complications associated with acute (n=1) or chronic (n=1) GvHD and two patients died during relapse eight and twelve months after PBSC. With a median follow-up of 15 months (range 1–65) thirteen out of seventeen patients (76 %) are alive and in remission. Conclusion: Early allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in AML patients with either poor risk karyotype or minor response to the first induction cycle.

Pretreatment cystatin C in children with malignancy: can it predict chemotherapy-induced glomerular filtration rate reduction during the induction phase?

Monitoring of kidney function is essential during chemotherapy. Serum creatinine is of limited value in early detection of renal insufficiency. The cystatin C level has been proved to be a good marker for detection of mild reduction in glomerular filtration rate. To evaluate the validity of the pretreatment serum cystatin C level in predicting significant reduction of the glomerular filtration rate during the induction phase of chemotherapy. Serum levels of cystatin C and creatinine and corrected creatinine clearance were assessed in 34 children with different types of malignancy just before the start of chemotherapy and again in 33 of them 1 month later. Patients were compared with 14 healthy controls of matched age and sex. Before chemotherapy, all patients when compared with controls had normal levels of cystatin C (P = 0.1) and creatinine (P = 0.62) and normal corrected creatinine clearance (P = 0.76). One month after chemotherapy, patients showed a significant increase in their cystatin C levels (P < 0.001) and a significant decrease in their corrected creatinine clearance (P < 0.001). However, creatinine levels did not change significantly (P = 0.65). Corrected creatinine clearance negatively correlated significantly with both cystatin C and creatinine levels (r = -0.622, P < 0.001; r = -0.346, P = 0.045, respectively) before chemotherapy and also 1 month after chemotherapy (r = -0.577, P < 0.001; r = -0.45, P = 0.009, respectively). When pretreatment levels of cystatin C and creatinine were used to predict patients who developed a reduction in corrected creatinine clearance of more than 20% after therapy, only the cystatin C level was statistically significant (P = 0.03). A cutoff point of 0.57 mg/L with sensitivity of 77.8%, specificity of 63%, and overall accuracy of 74% was suggested. Children with malignant diseases develop significant reduction in their glomerular filtration rate during the induction phase of chemotherapy, although their serum creatinine level may not change significantly. Cystatin C, as a more sensitive marker than creatinine for the assessment of glomerular filtration rate, can be used to predict patients who would have a higher risk of renal impairment during the induction phase of chemotherapy and who thus would require more frequent renal function assessment to consider adjustment of the chemotherapy dose if indicated.

Cystatin C as a Sensitive Marker of Nephrotoxicity in Children with Different Malignant Diseases During Induction Phase Of Chemotherapy

Background: Monitoring of kidney essential during the course of chemotherapy. Serum creatinine is of limited value in early detection of renal insufficiency. Cystatin C has proved to be a good marker for detection of early reduction in glomerular filtration rate (GFR). Objectives: To assess serum cystatin C in children receiving chemotherapy and to compare its sensitivity with serum creatinine in detecting early reductions in GFR. Methods: Serum cystatin C (Cc.), serum creatinine (Cr.) and corrected creatinine clearance (c.Cr.cl) levels were assessed in 34 children with different types of malignancy just before the start of chemotherapy and again in 33 of them one month later. Patients were compared to 14 healthy controls of matched age and sex. Results: Before the start of chemotherapy, all patients when compared to controls had normal Cc [median (IQR) = 0.57 (0.4-0.7) vs 0.4 (0.32-0.66) mg/L, P = 0.1], Cr. [median (IQR) = 0.7 (0.6-0.8) vs 0.7 (0.57-0.8) mg/dl, P = 0.62], and c.Cr.cl [median (IQR) = 115.35 (104.4-137.1) vs 115.8 (111.5-130.9) ml/min/1.73m², (P ˂ 0.001) and a significant decrease in their c.Cr.cl (P ˂ 0.001). On the other hand their serum Cr. Levels did not change significantly (p = 0.65).c.Cr.cl negatively correlated with both Cc and Cr (r = -0.622, p ˂ 0.001), (r = -0.346, p = 0.045) respectively before the start of chemotherapy and also after chemotherapy (r = -0.577, p ˂ 0.001) and (r = -0.45, p = 0.009), repectively. When pretreatment levels of Cc and Cr were used predict patients who developed ˃ 20% reduction in GFR after therapy, only Cc was statistically significant (P = 0.03). A cut off point of 0.57 mg/L with sensitivity of 77.8%; specificity of 63%, and an overall accuracy of 74% was suggested. Conclusions: Children with malignant diseases develop significant reduction in their GFR during the induction phase of chemotherapy despite the fact that their serum creatinine level may not change significantly. Cystatin C as a more sensitive marker than creatinine in detecting mild reduction in GFR can be used to predict patients who will develop renal impairment during the induction phase of chemotherapy.

Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia.

More than 95% of children with B-lineage acute lymphoblastic leukemia (ALL) achieve a clinical remission after the induction phase of chemotherapy (first 28 days) as evaluated by morphologic criteria. However, relapse occurs in approximately 30% of these children. The objective of this study was to determine whether the outcome of patients in clinical remission at the end of induction therapy could be predicted using a highly sensitive method to detect residual disease. All children diagnosed with B-lineage ALL at the Children's Hospital of Philadelphia during a 2-year period were eligible. The extent of residual leukemia was quantitated in remission marrow samples obtained at the end of induction therapy in 44 children using a phage clonogenic assay in association with complementarity-determining-region 3 (CDR3)-polymerase chain reaction (PCR). Residual disease was a significant predictor of outcome independent of WBC count, age, or sex. The estimated relapse-free survival (RFS) during therapy was 50.4% (+/- 12.6%) for patients with high residual disease (> or = 0.6% leukemia cells among total marrow B cells) versus 91.9% (+/- 5.5%) for those with lower levels (P < .002). There were no significant differences in off-treatment RFS between patients with high or low residual disease who completed therapy in continuous remission (P = .82). The overall estimated RFS was 32.3% (+/- 11.6%) for patients with high residual disease versus 62.6% (+/- 10.7%) for patients with lower levels of residual leukemia cells, with a median follow-up of 5.3 years for patients in continuous remission (P < .008). PCR detection of high residual disease at the end of induction therapy identifies patients at increased risk for relapse during therapy.

Limited small cell lung cancer: prognostic significance of a complete response to the induction phase of chemotherapy followed by thoracic irradiation.

Limited-stage small cell lung cancer is frequently treated with induction combination chemotherapy (ICC), followed by consolidation with thoracic irradiation. It has been suggested that patients who do not have a complete response to ICC are unlikely to have control of occult distant metastasis and consequently have such a poor prognosis that thoracic irradiation is unlikely to be of benefit. To examine this hypothesis, 48 patients treated on prospective protocols who achieved a complete response to ICC or subsequently to thoracic irradiation were analyzed. Twenty-four patients had a complete response to ICC (CR-ICC), and 24 subsequently converted to complete-response status after thoracic irradiation (CR-TI). The two groups had similar prognostic factors and treatment. Comparing CR-ICC and CR-TI patients, survival was 40% versus 26% at 2 years and 35% versus 4% at 5 years, respectively (P less than .05). Freedom from distant metastasis was 41% at 5 years for the CR-ICC patients and 8% for the CR-TI patients (P less than .05). A modest number of CR-TI patients were long-term survivors, suggesting a value for thoracic irradiation as consolidation therapy.

Oral Trimethoprim/Sulfamethoxazole for Prevention of Bacterial Infection During the Induction Phase of Cancer Chemotherapy in Children

We conducted a randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral trimethoprim/sulfamethoxazole (TMP/SMX) in the prevention of bacterial infections in children with cancer. Sixty-three patients with acute leukemia were studied during the induction phase of chemotherapy; 28 patients with solid tumors who were starting intensive chemotherapy were also enrolled and treated for 2 months. There was no significant difference in the frequency of febrile episodes between the 43 children receiving trimethoprim/sulfamethoxazole and the 48 receiving placebo. However, when the group of 74 children who experienced granulocytopenia (absolute granulocyte count less than 500/microL) was analyzed separately, significant reductions in the frequencies of confirmed bacteremia (2.6% v 20.0%, P = .02) and febrile episodes (35.9% v 65.7%, P = .01) were observed in the trimethoprim/sulfamethoxazole group. Furthermore, life table analysis showed that children with leukemia receiving trimethoprim/sulfamethoxazole had significantly more days without fever and without bacteremia. No benefits from prophylaxis were recognized in the subgroup with solid tumors. Although the frequency of oral thrush was greater (P = .02) in the trimethoprim/sulfamethoxazole group (25.6%) than in the placebo group (6.3%), invasive fungal infection did not occur. Although the mean duration of granulocytopenia was greater among those receiving trimethoprim/sulfamethoxazole (13.7 v 9.0 days, P = .05), this did not appear to increase the overall risk for bacterial infection. These data suggest that trimethoprim/sulfamethoxazole reduces the frequency of bacteremia and febrile episodes in granulocytopenic children undergoing induction chemotherapy for acute leukemia.

Fibronectin C in acute leukaemia

Fibronectin C (FN:C) is thought to represent fibronectin complexed with other plasma proteins and can be detected by a crossed two-dimensional immunoelectrophoretic technique. While we have not detected this on examination of normal plasma, FN:C was found in 26 of 33 patients (79%) with acute leukaemia at diagnosis. FN:C persisted throughout the induction phase of chemotherapy and disappeared only when a complete remission was obtained in 16 of 17 FN:C+ patients. FN:C has reappeared in the only patient whose leukaemia has relapsed to date. FN:C was present in both acute non-lymphoblastic (85%) and acute lymphoblastic leukaemia (50%). Leukaemia remission rates were similar in patients who were FN:C+ or FN:C- (69% and 57%). Evidence is presented to suggest that the composition of FN:C is partially related to the binding of fibrinogen/fibrin to fibronectin in plasma. No significant difference in in vivo activation of coagulation was detected between FN:C+ and FN:C- patients. There was no correlation between the presence of FN:C and plasma fibronectin levels.

Combined modality therapy for advanced, diffuse lymphocytic and histiocytic lymphomas

Forty-six previously untreated patients with advanced aggressive non-Hodgkin's (34 poorly differentiated and mixed diffuse, 8 histiocytic and 4 undifferentiated) were treated with a 3 phase combined modality program employing cyclophosphamide (C), hydroxyl-daunomycin (H), vincristine (O), prednisone (P), procarbazine (P) [CHOP(P)] combination chemotherapy in an initial induction phase, radiotherapy and nonmarrow toxic chemotherapy as a second consolidation phase, followed by a third phase of CHOP(P) chemotherapy for four more cycles. Long-term maintenance therapy was not given. High dose involved field radiation in phase II was limited to volumes encompasing less than 50% of the marrow bearing skeleton. The large majority of patients (82%) had such widespread involvement that this limitation precluded the use of local radiation and were treated instead with a mean of 132 rad of fractionated total body irradiation (TBI). Thirty-eight patients (83%) achieved complete remission. Twenty-nine (66%) of the 44 patients evaluable for follow-up, and 22 (61%) of the 36 patients receiving TBI, remain alive in complete remission for observation periods of up to 26 months.

The Definitive Treatment of Children with Acute Leukemia

Current therapy has resulted in improved prognosis in previously untreated children with acute lymphocytic leukemia less than 16 years of age. The induction phase of chemotherapy should include the use of at least prednisone and vincristine. This combination should result in a hematologic remission in about 90 per cent of the patients. The efficacy of the addition of either L-asparaginase or daunomycin, the consolidation phase or the periodic readministration of induction drugs has not been established. Specific central nervous system treatment, early in the course of therapy, is an integral component of recently reported effective protocols. Several modalities of prophalytic central nervous system therapy have been utilized. These include cranial irradiation plus intrathecal methotrexate, craniospinal irradiation and intrathecal methotrexate alone. An encephalopathy syndrome has been reported as a complication in 10 to 66 per cent of these patients. The most effective form of central nervous system therapy, associated with the least toxicity, has not been established. Maintenance chemotherapy should include a combination of two or more drugs. Complications are numerous, and include hematopoietic depression, immunosuppression, overwhelming infections, and, possibly, the development of secondary primary cancers. In the most successful protocols maintenance chemotherapy has been administered for 3 years. Because of the potential significant toxicity there is a need to define the optimal duration of maintenance therapy. Psychological complications developing in a patient with a disease now considered a potential long term chronic illness, rather than a disease once considered universally fatal, are also discussed. The possibility of an immunologic deficiency allowing for the initial development of acute lymphocytic leukemia and the role of immunotherapy are presented. While the use of intensive combination chemotherapy and specific central nervous system prophylactic therapy have resulted in an improved prognosis in childhood acute lymphocytic leukemia, because of a significant incidence of failures, a standardized single form of therapy has not been established.