Severe Treatment-related Toxicity Research Articles

Two Cases of Chronic Active Epstein-Barr Virus Infection (CAEBV) Successfully Treated with Allogeneic Bone Marrow Transplantation and Induction of Specific Cytotoxic T Lymphocyte (CTL).

Chronic active Epstein-Barr virus infection (CAEBV) is a heterogenous EBV-related disorder, characterized by clonal expansion of EBV-infected T or NK cells. Although CAEBV is a high mortality and morbidity disease with life-threatening complications, effective treatment regimens have not yet been established. The pathogenesis and etiology of CAEBV are not well characterized. The clonal expansion of EBV-associated T or NK cells has been suggested to play important roles in the pathogenesis of CAEBV. It is not clear why EBV-associated abnormal cells cannot be excluded, because of a factor on the virus side or a function on the host side. We report two cases of CAEBV in which allogeneic bone marrow transplantation (BMT) was performed soon after diagnosis. After BMT, the EBV genome titer decreased as cytotoxic T lymphocyte (CTL) activity gradually increased.Case 1: A five-year-old boy had exhibited prolonged fever, lymphadenopathy, and severe liver dysfunction for more than 6 months. Clonally proliferating EBV-infected T cells and abnormally high titers of EBV-related antibodies were detected. No EBV-specific CTLs were detected. The patient was given a diagnosis of T-cell type CAEBV and he received BMT (the donor was his 1-locus mismatched mother) 6 months after diagnosis. Severe treatment-related toxicity did not occur. After BMT, the EBV genome titer gradually decreased as the CTL activity increased. At 2 months after BMT, the EBV genome titer of the patient was nearly negative.Case 2: A two-year-old girl had exhibited a persistent fever of unknown etiology and hepatosplenomegaly. Abnormally high titers of EBV-related antibodies were detected and NK cells in her peripheral blood contained a high EBV genome titer. The EBV-specific CTL levels were low. She received BMT from an unrelated donor 3 months after diagnosis. Toxicity other than grade 2 graft-versus-host disease was not detected. After BMT, the EBV genome titers decreased gradually as the CTL activity increased.Conclusion: These cases suggest that not only high-dose chemotherapy as a preconditioning treatment of BMT, but also that increased CTL activity to eliminate virus-infected cells might be effective. Additional cases should be studied to establish effective treatments.

R-CHOP Modified with Pegilated Lyposomal Adriamycin in Elderly Diffuse Large B-Cell Non Hodgkin's Lymphoma (DLBC-NHL) Therapy: An Attempt To Reduce Toxicity in Patients with Comorbidity.

The Combination of Rituximab and CHOP (R-CHOP) is the golden standard in young and elderly NHL therapy, safe and effective. We included pegylated lyposomial Adriamycin (Caelyx®) instead of conventional Adriamycin in R-CHOP regimen in order to reduce myocardic and organ toxicity and to enhance doxorubicin uptake in tumour mass in advanced stage DLBC-NHL of elderly patients with comorbidity. This study is a retrospective study including patients of two haematology centers. We analyzed 34 DLBCNHL patient treated with R-CCOP (Rituximab 375mg/sqm day 0, Caelyx® 30 mg/sqm day 1, cyclophosphamide 750 mg/sqm day 1, Vincristine 1 mg/sqm day 1, Prednisone 100 mg/day, days 1–5, recycle every 21 days). The median number of administered cycles was 6 (Range 4–11). G-CSF was administered according to international guidelines Their median age was 74.5 years old (Range 65–87), M/F:20/14, 19/34 (55%) patients presented stage III– IV disease. 8 (23%) had B symptoms and 11 (32%) extranodal disease.12/34 (35%) patients had IPI high-intermediate and 11/34 (32%) high. 17/34 (50%) showed comorbidity (hepatitis C, NIDDM, severe hypertension, aortic valve disease, atrial fibrillation, chronic renal failure). Median follow-up was 26 months (Range 9–36). Overall (OS) and progression-free survival (PFS) at 36 months were calculated using Kaplan-Mayer method. After R-CCOP therapy we obtained the complete remission in 24/34 (70%) of patients, a very good partial remission in 2/34 (5%). The disease progressed in 3/34 (8%). Five out of 34 (14%) dead (3 of these for disease progression). No severe treatment-related toxicities were observed, except G3-G4 WHO neutropenia in 17 patients (50%) and cardiotoxicity in 2 patients (6%) with pre-existing cardiopathy (bradycardia and atrial fibrillation with high heart rate respectively). Myocardial function was evaluated by 2D echocardiogram before and after chemotherapy treatment and was not impaired by pegylated lyposomial Adriamycin administration. 3% of patients presented severe mucositis and 9% non-fatal infections. We did not observe any thrombocytopenia, In our study OS and EFS at 36 months were respectively 83.7% (95%CI 70.4–97%) and 56% (95%CI 27–85%).Non-responding patients had extranodal, stage IV disease with B symptoms. Nevertheless, they maintained chemosensitivity to a second-line therapy. In elderly B-NHL patients with advanced stage of disease and comorbidity, R-CCOP seems to be safe, feasible and effective. These results confirm and improve in a larger cohort of patients those reported by Zaja, Tulpule and Coiffier in their previous series (see table).Zaja et alTulpule et alGiordano et alCoiffier et alTreatmentR-COP-Caelyx x6R-COP-Caelyx x8R-COP-Caelyx x4-11R-CHOP x8Patients291934202Caelyx mg/sqm304030\\Doxorubicin mg/sqm\\\\\\50Age (median)695174.569IPI (L/IL)38%47%32%46%IPI IH/H62%53%68%54%OR76%100%76%82%CR59%80%71%76%2y EFS65.5%NA(56% 3y)60%TRM00012/202 (6%)Grade III/IV toxicityNeutropenia86%68%50%91%Thrombocytopenia3%5%0%NAMucositis3%0%3%3%Infection3%0%9%12%Cardiotocicity0%0%6%*8%* in 2 pts with preexisting cardiopathy

Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer

The humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody matuzumab (formerly EMD 72000) is active against pancreatic cancer in preclinical studies. This phase I study assessed the safety and potential benefit of combined treatment with matuzumab and standard-dose gemcitabine. Three groups of chemotherapy-naive advanced pancreatic adenocarcinoma patients (n=17) received escalating doses of matuzumab (400 mg weekly, 800 mg biweekly, or 800 mg weekly) and gemcitabine (1000 mg m–2 weekly in weeks 1–3 of each 4-week cycle). Toxicity, antitumour activity, pharmacokinetic (PK) parameters, and pharmacodynamic (PD) markers in skin biopsies were evaluated. Severe treatment-related toxicities were limited to grade 3 neutropenia (n=3), leucopenia (n=1), and decreased white blood cell count (n=1). Common study drug-related adverse events were skin toxicities (grade 2=6, grade 1=7) and fever (grade 1=4). Matuzumab inhibited phosphorylated EGFR and affected receptor-dependent signalling and transduction; effects were seen even in the lowest-dose group. Pharmacokinetic data were consistent with results of matuzumab monotherapy. Partial response (PR) or stable disease occurred in eight of 12 evaluated patients (66.7%), with three PRs among six evaluated patients in the group receiving 800 mg weekly. Matuzumab in biologically effective doses with standard gemcitabine therapy appears well tolerated. The combination is feasible and may have enhanced activity.

Raltitrexed and Radiotherapy as Adjuvant Treatment for Stage II-III Rectal Cancer: A Feasibility Study

Adjuvant 5-FU chemotherapy plus radiotherapy represents the standard treatment for radically resected rectal cancer at high risk of relapse according to the NIH Consensus Conference. The therapeutic gain was obtained with a high rate of severe treatment-related toxicity and a suboptimal patient compliance with this regimen. Raltitrexed is a specific thymidylate synthase inhibitor with a convenient administration schedule, acceptable toxicity and radiosensitizing properties, as the published phase I trials in combination with radiotherapy have shown. The aim of this prospective multicenter phase II study was to evaluate the feasibility, gastrointestinal and hematological acute toxicity of raltitrexed in combination with radiotherapy in rectal cancer patients. From September 2000 to June 2004, 50 patients with radically resected stage II-III rectal adenocarcinoma were treated. All patients were evaluable for compliance and acute toxicity. Within 45-60 days of surgery, each patient underwent concomitant adjuvant radiochemotherapy. Radiotherapy was administered to the pelvis (plus perineum after abdominoperineal resection) with photon beam energy exceeding 5 MV, 3-4 fields, 45 Gy/25 fractions/5 weeks plus a boost delivered to the site of resected disease with 3-4 fields, 9 Gy/5 fractions/1 week to a total dose of 54 Gy. The boost dose was administered after complete exclusion of the small bowel from the treatment volumes; if this was not possible a total dose of 50.4 Gy was given. Raltitrexed was administered intravenously at a dose of 3 mg/m2 as a bolus injection on days 1 and 22 of radiotherapy one hour before treatment, for a total of two cycles. Each patient underwent weekly clinical evaluation and laboratory tests. Toxicity was assessed by the WHO scale. Forty-five (90%) patients completed the established treatment. Acute severe toxicity included grade III proctitis in 4/50 (8%), grade III-IV diarrhea in 4/50 (8%), grade III perineal dermatitis in 4/50 (8%) and grade III leukopenia in 2/50 (4%) patients; five patients (10%) experienced a transient grade Ill increase in their liver biochemistry values. Our data related to acute toxicity and patient compliance proved the feasibility of this adjuvant radiochemotherapy treatment. A longer follow-up is necessary to evaluate the effectiveness of this new regimen in terms of disease-free and overall survival.

Autologous transplantation in patients with relapsed or high-grade follicular lymphoma provides long term disease-free survival and best median duration of response

The best treatment option for patients with relapsed or high-grade follicular lymphoma (FL) is unknown. In spite of major advances in the therapy for FL, disease-free survival remains short, and median time to progression is just over a year. Autologous stem cell transplantation in patients with relapsed FL is safe and appears to improve disease-free survival. In an attempt to examine whether autologous stem cell transplantation provides long-term disease control in patients with relapsed or high-grade FL, we retrospectively evaluated our experience and analyzed the outcomes of autologous stem cell transplantation in patients with FL from 1991 to 2003. Seventeen men and seven women (n=24) of median age 47.5 years (range 28-64 years) were treated. Three patients with high-risk FL were in first remission. Twenty-one patients were salvaged after relapse with second-line chemotherapy. Of these, 14 were in CR at the time of transplantation, and seven patients were transplanted with active disease. Bone marrow was used in six patients as the source of stem cells prior to 1995 and peripheral blood stem cells were used in 18 patients. Twenty-three of 24 patients engrafted (96%). Median time for neutrophil recovery was 11.5 days (range 9-35 days) and 15 days (range 10-40 days) for platelets. Median duration of follow-up was 6 years (range 7 months-8 years). Of the 24 patients, six have died-with one patient death due to transplant-related pulmonary complications. Overall survival (OS) and disease-free survival (DFS) of all evaluable patients were 71.6 and 40%, respectively. Median duration of response was 4.3 years. OS and DFS in patients transplanted in CR were 80 and 57%, respectively. For those transplanted with disease, a complete response was achieved in 43% of patients, with the OS and DFS of 57 and 19%, respectively. Disease status at transplantation was not a significant variable for survival (p>0.3). Three patients developed moderate to severe treatment-related toxicity, two with grade III mucositis and one with life-threatening infection. When these results are compared with historical controls or patients treated with other modalities, autologous stem cell transplantation appears to be providing the longest disease-free survival and best duration of response.

The outcome and the adverse effect of postoperative radiotherapy for keloids: A prospective study with a total dose of 20 Gy

Until 1994, keloids had been treated with resection and postoperative radiotherapy with a various radiation dose in our institution. The most frequent dose used was 16 Gy and 24 Gy. In a retrospective evaluation, the relapse rate and the incidence of hyperpigmentation and/or telangiectasis was 49% and 15% at 16 Gy, and 8% and 29% at 24 Gy, respectively, suggesting a dose-response relationship both in keloid control and morbidity. Since 1995, the total dose was fixed to 20 Gy in 5 fractions, in expectation of preserving the cosmetic outcome without compromising on the control rate. We report in the present study the outcome and the adverse effects in patients with postoperative keloids treated with 20 Gy. From January 1995 to May 2003, 235 keloids in 181 patients (62 male and 119 female, median age 33 years old) received postoperative radiotherapy with a total dose of 20 Gy in 5 fractions over 9 to 14 days. Soft X-rays (55 or 100 kVp) or electron beams (5 or 7 MeV) were used. The 90% isodose target area included the entire postoperative scar and any suture/puncture hole with a margin of 3–5 mm around the lesion. Non-target area was shielded by individually cut-out 1–2 mm lead sheet. The size and height of keloid, cosmetic status, symptoms, and adverse effects were prospectively evaluated every several months after radiotherapy. The median follow-up period was 21.4 months (range 6–81 months). All patients completed the scheduled treatment. 27 out of 235 keloid scars (11%) relapsed. A univariate and a multivariate analysis with various prognostic factors showed that the relapse rate was significantly correlated with the site of keloids. The relapse rate was 15% for the keloid scars under high stretch tension (e.g. anterior chest wall, shoulder, and suprapubis), while 0% for those without high tension (e.g. face, neck, earlobes, hip, and lower limbs). Cosmetic status was judged to be excellent in 48 lesions (20%), good in 152 lesions (65%), and fair in 24 lesions (10%). Among 191 lesions, which caused itching and/or pain before treatment, symptomatic relief was achieved in 177 lesions (93%). No severe (grade 3 or above) treatment-related toxicity was observed. The incidence of hyperpigmentation and/or telangiectasis was 10%. Comparing the present results in the patients treated with 20 Gy to the previous results in the patients treated with 16 and 24 Gy in our institute, the keloid relapse rate after 20 Gy was significantly lower than that after 16 Gy and comparable to that after 24 Gy, while the incidence of adverse effects after 20 Gy was comparable to that after 16 Gy and lower than that after 24 Gy. We concluded, therefore, 20 Gy is the optimal total dose for the postoperative radiotherapy of keloids. The extremely low relapse rate for the keloids on the loose skin suggested that the use of a lower total dose may be warranted for these lesions

Increased expression of pro-inflammatory cytokines as a cause of lung toxicity after combined treatment with gemcitabine and thoracic irradiation

Background and purpose Preclinical evidence suggesting gemcitabine potentiates the anti-tumor effects of irradiation has resulted in clinical trials to evaluate the treatment efficacy of gemcitabine and concurrent thoracic irradiation in non-small-cell lung cancer (NSCLC). Although these studies demonstrated favorable tumor response, this combined treatment modality was accompanied by severe treatment-related toxicities predominantly of the lung. In an attempt to elucidate the determinants of lung toxicity for gemcitabine, we analyzed the expression of the pro-inflammatory cytokines TNF-α, IL-1α and IL-6 in the lung tissue of mice treated with gemcitabine and concurrent thoracic irradiation. Materials and methods Four study groups were defined: C57BL/6J mice that received neither irradiation nor gemcitabine (NT-group), those that received gemcitabine (120 mg/kg intraperitoneal, i.p.) but no irradiation (GEM-group), those that underwent thoracic irradiation (12 Gy) without gemcitabine (XRT-group), and those that received both gemcitabine (120 mg/kg i.p., 2 h before irradiation) and thoracic irradiation (GEM/XRT-group). The mice were sacrificed at 1 h, 1 and 3 days, 1, 2 and 4 weeks post-treatment (p.t.). The mRNA expression of TNF-α, IL-1α and IL-6 in the lung tissue was quantified by competitive RT-PCR. The cellular origin of the cytokine expression was identified by immunohistochemistry. The cytokine expression was correlated with histopathological alterations. Results The TNF-α, IL-1α and IL-6 expression in the lung tissue of the GEM/XRT mice was clearly higher at all assessment time points compared to the NT mice (statistically significant at 1 h, 1 and 3 days, 1, 2 and 4 weeks p.t.), XRT mice (statistically significant at 1 week p.t.) or GEM mice (statistically significant at 1 h, 1 and 2 weeks p.t.). Maximal treatment-induced cytokine expression in the lung tissue of the GEM/XRT mice occurred already at 1 week p.t. (TNF-α: 30.9±5.3/IL-1α: 28.3±5.0/IL-6: 4.9±0.1 times basal level), and coincides with pathohistologically discernable interstitial pneumonitis. The elevated levels of TNF-α and IL-1α have been found to correlate with immunohistochemical staining of the bronchiolar epithelium and predominantly of inflammatory cells. Conclusions Our data provide evidence that the increased expression of pro-inflammatory cytokines and the induction of a cytokine-triggered inflammatory response may be a determinant of the observed elevated lung toxicity after concurrent treatment with gemcitabine and thoracic irradiation.

A long term follow up study of autologous transplantation for follicular lymphoma: a single center experience

Appropriate timing of transplant in the management of follicular lymphoma (FL) is not clear. We retrospectively evaluated our experience of autologous transplantation in patients with FL from 1991 to 2003. Seventeen males and 7 females (n = 24) of median age 47.5 years (range, 28–64 years) were treated. Three patients were in first remission. Twenty one patients were salvaged after relapse with second line chemotherapy. Of these, 14 were in CR or very good PR at the time of transplantation, and 7 patients were transplanted with active disease. Bone marrow was used in 6 patients as the source of stem cells prior to 1995 and peripheral blood stem cells were used in 18 patients. The median CD34+ cell dose was 2.97 × 106/kg (range, 2.22–7.49 × 106/kg). Twenty-three of 24 patients engrafted (96%). Median time for neutrophil recovery was 11.5 days (range, 9–35 days) and 15 days (range, 10–40 days) for platelets. Median duration of follow up was 6 years (range, 7 month–8 years). Of the 24 patients, 6 had died. One patient died from transplant related pulmonary complication. Overall survival (OS) and disease free survival (DFS) of all evaluable patients were 71.6% and 40%. Median duration of response was 4.3 years. OS and DFS in patients transplanted in CR were 80% and 57%. For those transplanted with disease, a complete response was achieved in 43% of patients, with the OS and DFS of 57% and 19 % respectively. Status at transplantation was not a significant variable for survival (p > 0.3). Three patients developed moderate to severe treatment related toxicity; 2 with Grade III mucositis and 1 with life threatening infection. In our experience, high dose therapy with autologous stem cell transplantation in patients with high risk or relapsed/refractory FL has little toxicity and appears to be effective. Those with more advanced disease may require additional approaches to achieve and maintain remission.

Efficacy and safety of imatinib mesylate (Glivec™) in combination with interferon-α (IFN-α) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL)

Imatinib has marked antileukemic activity in advanced Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), but secondary resistance develops rapidly, reflecting the limitations of single-agent therapy. Experimental data suggest that interferon-alpha (IFN-alpha) enhances the antileukemic activity of imatinib. We therefore examined combined imatinib and low-dose IFN-alpha in six patients with Ph+ALL who were ineligible for stem cell transplantation. All patients had received imatinib for 0.5-4.8 months prior to IFN-alpha, for relapsed (n=3) or refractory (n=1) Ph+ALL or as an alternative to chemotherapy following severe treatment-related toxicity (n=2). Five patients were in hematologic remission (CR) with minimal residual disease (MRD+), one patient was refractory to imatinib. Four of the five MRD+ patients are alive in CR after a median treatment duration of 20 (11-21) months. Two of these patients are in continuous CR 21 months after imatinib was initiated, while the other two patients experienced an isolated meningeal relapse that was successfully treated with additional intrathecal chemotherapy. Sustained molecular remissions were achieved in three patients and are ongoing 13 and 10.5 months after central nervous system (CNS) relapse and 6 months after starting concurrent IFN-alpha and imatinib, respectively. Marrow relapse occurred in one of the five MRD+ patients. Combination treatment was associated with a complete marrow response of 5 months duration in the imatinib-refractory patient. Imatinib combined with low-dose IFN-alpha may achieve prolonged hematologic and molecular remissions in a subset of patients with advanced Ph+ALL, who are not candidates for allogeneic SCT. CNS prophylaxis is necessary and may enhance the antileukemic activity of imatinib and IFN-alpha.

Therapeutic Management with Adriamycin-Containing Chemotherapy and Radiotherapy of Monostotic and Polyostotic Primary Non-Hodgkin's Lymphoma of Bone in Adults

The best treatment of primary lymphoma of bone (PLB) remains underfined. We reviewed 15 patients with monostotic PLB and 8 with polyostotic PLB. Twenty of the patients were suitable for analysis. All patients but 1 received adriamycin-containing chemotherapy in association with radiation therapy. Radiotherapy for monostotic cases consisted of 40 Gy to long bones, followed by a boost to 45 Gy to bulky lesions or 40–45 Gy to whole jut bones. In cases of polyostotic PLB, bulky sites, fractured lesions, or sites with a high risk of fracture were irradiated with a median dose of 38 Gy. All patients with monostotic disease achieved complete remission (CR): 10 patients were alive and relapsefree at the time of this writing, 1 other patient was alive following a relapse, and 1 patient died while relapse-free. The survival rate for the patients in the study at the time of this writing was 92% at 50 months. Four patients with polyostotic disease achieved CR. Three of them had only two adjacent sites of disease and were treated as cases of monostotic PLB. Two of these 3 patients are alive and relapse-free. Four patients with polyostotic disease achieved PR, relapsed rapidly, and died of progressive disease. The relapse site was invariably the skeleton. The survival rate for patients with polyostotic PLB at the time of writing was 25% at 40 months. No severe late treatment-related toxicity was observed. The treatment of patients with monostotic PLB with adriamycin-containing chemotherapy and whole-bone irradiation with 40 Gy, followed by a boost to 45 Gy to bulky sites, prevented local relapse and produced a more favorable outcome than the use of radiotherapy (RT) alone. Patients with multiple adjacent lesions that can be included within a single radiation field with acceptable toxicity should be treated as cases of monostotic PLB.