Last Cycle Of Chemotherapy Research Articles

Immunonutrition before and during radiochemotherapy: improvement of inflammatory parameters in head and neck cancer patients

Inflammatory, angiogenic and oxidative stress markers have been explored in head and neck squamous cell carcinoma (HNSCC) patients before and during radiochemotherapy. Furthermore, the effects of an oral supplementation containing amino acids, ω-3 fatty acids, ribonucleic acids, vitamins, and antioxidants on biological markers and acute toxicities were investigated. Thirty-one patients with non-metastatic stage III or IV HNSCC treated with concomitant radiochemotherapy were recruited. A nutritional support (Oral Impact) was given during 5 days before each cycle of chemotherapy. Biological samples were collected at baseline, after 5 days of oral supplementation and before the last cycle of chemotherapy. Acute phase proteins levels, proteomic cytokines determination and urinary isoprostanes levels were used as inflammatory and oxidative stress biomarkers. Toxicities were followed up during radiochemotherapy. At baseline, median levels of inflammatory (CRP 9.8 mg/l [0.8-130.1], IL-6 4.2 pg/ml [0.7-126.5]), pro-angiogenic (VEGF 229.5 pg/ml [13.1-595.9]) and pro-oxidative stress (urinary isoprostanes 118 pmol/mmol creatinine [51-299]) markers were increased. Decrease in CRP (p = 0.002) and α-1 acid glycoprotein (p = 0.020) levels were observed after 5 days of oral supplementation. During radiochemotherapy, no significant variation of inflammatory markers was reported, and a low incidence of severe acute mucositis was noted. Stage III or IV HNSCC patients are characterised by a pro-inflammatory, pro-angiogenic and pro-oxidative status. Nutritional support could improve this inflammatory state and could prevent severe acute mucositis.

Rare pulmonary primitive neuroectodermal tumor metastasizing to the right atrium: a case report

A 28-year-old man complained of intermittent irritable dry cough for 2 months with occasional bloody sputum. Positron emission tomography-computed tomography (PET-CT) suggested multiple heterogeneous soft tissue masses in the inferior lobes of both lungs, with heterogeneous increases in 18F-FDG uptake. No metabolic disorders were found in the rest of the body. CT-guided percutaneous lung puncture and biopsy and immunohistochemical study confirmed pulmonary primitive neuroectodermal tumor (PNET). PNET is characterized by small round blue cells and positive CD99 expression. After six cycles of chemotherapy with ifosfamide, dacarbazine and cisplatin, the lesions diminished substantially. At 2 months after the last cycle of chemotherapy, the patient complained of exertional dyspnea. PET-CT and echocardiogram suggested a space-occupying lesion in the right atrium. Autopsy revealed that this space-occupying lesion had the same pathomorphology and immunophenotype with pulmonary PNET, suggesting metastasis of pulmonary PNET to the right atrium. Here, we reported this rare case of pulmonary PNET metastasizing, instead of direct infiltrating or extending, into the heart.

Fatal hepatitis B reactivation treated with entecavir in an isolated anti-HBs positive lymphoma patient: A case report and literature review

Hepatitis B virus (HBV) reactivation is a well-recognized complication that occurs in lymphoma patients who undergo chemotherapy. Only very few cases of HBV reactivation in patients with isolated antibody against hepatitis B surface antigen (anti-HBs) have been reported. We present a case of a 78-year-old woman diagnosed with diffuse large B cell non-Hodgkin's lymphoma who only displayed a positive anti-HBs, as the single possible marker of occult HBV infection, before starting therapy. She was treated with several chemotherapeutic regimens (including rituximab) for disease relapses during 3 years. Forty days after the last cycle of chemotherapy, she presented with jaundice, markedly elevated serum aminotransferase levels, and coagulopathy. HBV serology showed positivity for HBsAg, anti-HBc and anti-HBs. HBV DNA was positive. Antiviral treatment with entecavir was promptly initiated, but the patient died from liver failure. A review of the literature of HBV reactivation in patients with detectable anti-HBs levels is discussed.

Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II–IIIc breast cancer

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC→T) every 3weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC→T (α=0.05, β=80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC→T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P=0.02). Further evaluation of NOV-002 in a randomized study is warranted.

Progressive pericardial effusion during chemotherapy for advanced Hodgkin lymphoma

A 48 year-old man, previously in excellent health, presented with several weeks of diffuse pruritus and night sweats as well as a cervical mass unresponsive to antibiotics. A biopsy of the supraclavicular lymph node demonstrated CD30-positive, CD15-negative classical Hodgkin lymphoma (HL), nodular sclerosing subtype (Fig. 1). There was a normal cardiac silhouette and widened mediastinum on a chest X-ray performed at that time (Fig. 2a,b). A staging positron emission tomography/computer tomography (PET/CT) revealed extensive FDG-avid cervical, supraclavicular, mediastinal as well as periportal adenopathy. There was no lymphoma in the bone marrow biopsy, confirming the diagnosis of stage IIIB disease according to Ann Arbor classification. The white blood cell count was 6.6 3 10/L, absolute lymphocyte count 900 3 10/L, hemoglobin 13.6 g/dL, erythrocyte sedimentation rate 37 mm/h and albumin 4.0 g/dL. The patient was offered treatment with standard ABVD chemotherapy for six cycles, with a plan for interim reassessment after two cycles. The patient had advanced HL with two negative prognostic factors based on the International Prognostic Score, corresponding to a 67% chance of 5-year freedom from progression of disease and overall survival of 81% [1]. Despite superior results in advanced HL reported in the HD9 study with dose-escalated BEACOPP, [2] its adoption has been hampered by high rates of infertility, infections, and secondary leukemias [3]. Recent data suggest attenuated difference between BEACOPP and ABVD if stem cell transplantation is planned for the minority of patients experiencing a relapse [4]. This area remains a subject of intense controversy. Moreover, evidence of complete response by PET/CTafter two cycles of ABVD appears to confer excellent prognosis, even though decision-making based on such evaluation is still subject to prospective randomized trials. This paradigm underscores the focus on identifying the patients with good or poor outcomes with standard therapy rather than treating everyone with maximally aggressive protocols. Evaluation of cardiac function is recommended before administration of doxorubicin and the patient had an incidental negative stress echocardiogram 9 months before the lymphoma diagnosis, without evidence of decreased ventricular function or pericardial disease. Similarly, he had a normal pulmonary function test including diffusion lung capacity before receiving bleomycin. A complete clinical and radiographic response was confirmed at the time of 2-month interim restaging. There were no major side effects of chemotherapy except for Grade 2 neutropenia, aphtous ulcers, and toenail onchomycosis treated with oral terbinafine and nail avulsion. On the restaging PET/CT a moderate, circumferential pericardial effusion was noted, retrospectively present on the initial scan, without any fluorodeoxyglucose (FDG) activity in the pericardial sac. Since the patient had no respiratory or cardiovascular symptoms, therapy was continued as planned without interruption. During the last cycle of chemotherapy the patient reported transient bilateral swelling of the metacarpophalangeal joints and ankles. This was accompanied by a recurrent, atypical left-sided chest discomfort at rest and with exertion. There was no difference with position or respiration. He had no palpitations, dyspnea, dizziness, fever or night sweats, and no numbness or paresthesiae. No other musculoskeletal problems, recent travel, or tick bites were reported. Examination revealed normal vital signs with mild tachycardia (heart rate 89 beats per minute), no adenopathy or discernible edema in the hands, and only mild swelling of the ankles. Heart sounds were normal with no gallop, murmur, or rub. The symptoms subsided after a few days. Immediately after the last dose of chemotherapy, the lower extremity edema as well as cough and a steady left-sided chest discomfort recurred. The electrocardiogram (EKG) showed normal sinus rhythm at the rate of 84 beats per minute with a QRS interval of 90–110 msec (Fig. 2d). There were no classic ST or T wave changes seen in acute pericarditis. There was no diagnostic low voltage or electrical alternans to suggest a large, hemodynamically significant pericardial effusion. Cardiac troponin and creatinine kinase were repeatedly normal. A 2D echocardiogram revealed a circumferential pericardial fluid measuring up to 19 mm at end diastole consistent with moderate to large pericardial effusion (Fig. 2c). Early diastolic collapse of the right atrium was noted but no pericardial thickening or tamponade physiology. Chest X-ray confirmed enlargement of the transverse diameter of the heart with resolution of mediastinal adenopathy. The patient had a clinical syndrome of serositis with a progressive pericardial effusion. The electrocardiographic findings were non-specific. EKG findings in acute pericardi-

Induction chemotherapy with paclitaxel and cisplatin to concurrent radiotherapy and weekly paclitaxel in the treatment of loco-regionally advanced, stage IV (M0), head and neck squamous cell carcinoma. Mature results of a prospective study

Backgroundto evaluate activity and toxicity of a sequential treatment in advanced, non metastatic, mostly unresectable, head and neck squamous cell carcinoma.MethodsPatients with loco-regionally advanced or unresectable, head and neck cancer, were prospectively treated with 3 courses of induction chemotherapy followed by concurrent chemoradiation. Induction chemotherapy consisted of paclitaxel 175 mg/m2 day 1 and cisplatin 75 mg/m2 day 2, given every 3 weeks, to a total of three courses. Curative radiotherapy started 4 weeks after the last cycle of chemotherapy with the goal of delivering a total dose ≥ 66 Gy. During RT weekly paclitaxel (40 mg/m2) was administered.ResultsThe trial accrued 43 patients from January 1999 to December 2002. All patients received 3 courses of induction chemotherapy and the planned dose of radiotherapy. Thirty-eight patients were able to tolerate weekly paclitaxel during irradiation at least for 4 courses. After induction therapy there were 32 overall responses, 74.4% (23 partial and 9 complete); at completion of concomitant treatment overall responses were 42, 97.7% (20 partial and 22 complete). Median time to treatment failure was 20 months and the disease progression rate at 3 and 5 years was 33% and 23%, respectively. The median overall survival time was 24 months and 3 and 5 years overall survival rates were 37% and 26%, respectively. The major toxicity was mucositis.ConclusionsThis combined treatment was found to be feasible and active in advanced or unresectable, head and neck squamous cell carcinoma patients. Long-term results observed in this trial encourage to consider this approach in further investigation using newer radiation delivering technique and new molecularly agents.

The efficacy and safety of neoadjuvant chemotherapy +/− letrozole in postmenopausal women with locally advanced breast cancer: a randomized phase III clinical trial

This two-arm randomized clinical study aimed to evaluate the efficacy and safety of neoadjuvant concurrent chemotherapy and letrozole in postmenopausal women with locally advanced breast carcinoma. One hundred and one postmenopausal women aged 50-83 years with pathologically proven locally advanced (clinical stage T3, T4 and/or N2, N3) breast cancer were randomly assigned to receive neoadjuvant chemotherapy alone (control arm, n = 51) or neoadjuvant chemotherapy concurrent with letrozole 2.5 mg (study arm, n = 50). Chemotherapy consisted of a median 4 (range 3-5) cycles of intravenous 5-fluorouracil 600 mg/m(2), doxorubicin 60 mg/m(2), and cyclophosphamide 600 mg/m(2), every three weeks. All patients subsequently underwent modified radical mastectomy approximately two weeks after the last cycle of chemotherapy. Pathologic complete response rates were 25.5% and 10.2% in the study and the control group, respectively (P = 0.049). Similarly, clinical complete response rates were 27.6% and 10.2% in the study and the control group, respectively (P = 0.037). In the subgroup analysis of hormone receptor-positive cases, the complete response rates were more prominent in study group compared with control group. Common treatment-related side effects such as nausea, vomiting, bone marrow suppression, and mucositis were similar in both groups, but hot flush was more prevalent in study group compared with control group (P = 0.023). The addition of letrozole concurrently with neoadjuvant chemotherapy provides a higher clinical and pathologic response rates with acceptable toxicity compared with chemotherapy alone in postmenopausal women with locally advanced sensitive breast cancer.

Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on the Occurrence of Chemotherapy-Induced Early Menopause in Premenopausal Women With Breast Cancer

Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available. To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data. Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy. Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy). The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of -17% (95% confidence interval, -26% to -7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001). The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause. clinicaltrials.gov Identifier: NCT00311636.

Chemotherapy Definitions and Policies for Thymic Malignancies

Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat.1 Thymomas are usually localized to the anterior mediastinum and are frequently eligible for upfront surgical resection, which is the mainstay of the curative-intent treatment.1 However, approximately 30% of patients present with an advanced tumor at the time of diagnosis, with invasion of neighboring organs, dissemination to the pleura, the pericardium, or less frequently extrathoracic organs. In such cases, chemotherapy has been used both to reduce the tumor burden—possibly allowing subsequent surgery or radiotherapy—and to achieve prolonged disease control. Recurrence after resection may be similarly treated with chemotherapy. Thymic carcinomas, although rare, are usually already advanced at the time of presentation, and systemic therapy is important for almost all of these patients. Knowledge regarding chemotherapy for thymic tumors has mainly been based on retrospective series,2–9 although several prospective trials have also been conducted.10–21 These studies have clearly demonstrated the chemosensitivity of thymoma, and to a lesser extent thymic carcinoma, to various cytotoxic agents and combinations. However, details of patient selection are often lacking (either disease extent or general condition), and the intent of the treatment sequence is often vague. Adoption of a common language and definition of terms is crucial for the International Thymic Malignancies Interest Group (ITMIG) effort to develop a international prospective database of thymic tumors. The article by Huang et al.22 provides definitions for survival and endpoints for recurrences assessment and discusses how to measure response to treatment. Herein, we discuss additional points with regard to chemotherapy, including treatment sequence, general modalities, and impact of corticosteroids.

Tryptophan degradation in women with breast cancer: a pilot study

BackgroundAltered tryptophan metabolism and indoleamine 2,3-dioxygenase activity are linked to cancer development and progression. In addition, these biological factors have been associated with the development and severity of neuropsychiatric syndromes, including major depressive disorder. However, this biological mechanism associated with both poor disease outcomes and adverse neuropsychiatric symptoms has received little attention in women with breast cancer. Therefore, a pilot study was undertaken to compare levels of tryptophan and other proteins involved in tryptophan degradation in women with breast cancer to women without cancer, and secondarily, to examine levels in women with breast caner over the course of chemotherapy.FindingsBlood samples were collected from women with a recent diagnosis of breast cancer (n = 33) before their first cycle of chemotherapy and after their last cycle of chemotherapy. The comparison group (n = 24) provided a blood sample prior to breast biopsy. Plasma concentrations of tryptophan, kynurenine, and tyrosine were determined. The kynurenine to tryptophan ratio (KYN/TRP) was used to estimate indoleamine 2,3-dioxygenase activity. On average, the women with breast cancer had lower levels of tryptophan, elevated levels of kynurenine and tyrosine and an increased KYN/TRP ratio compared to women without breast cancer. There was a statistically significant difference between the two groups in the KYN/TRP ratio (p = 0.036), which remained elevated in women with breast cancer throughout the treatment trajectory.ConclusionsThe findings of this pilot study suggest that increased tryptophan degradation may occur in women with early-stage breast cancer. Given the multifactorial consequences of increased tryptophan degradation in cancer outcomes and neuropsychiatric symptom manifestation, this biological mechanism deserves broader attention in women with breast cancer.

Management of recurrent endodermal sinus tumor of the ovary associated with pregnancy

The patient was a 27-year-old woman (gravida 1, para 0) referred to our hospital for the recurrence of an ovarian endodermal sinus tumor at 33 weeks gestation. Laparotomy with a left salpingooophorectomy and partial omentectomy was performed 33 months prior at her local hospital (unstaged surgery). Six cycles of chemotherapy were performed after surgery: two cycles with carboplatin and cyclophosphamide (CC) and four cycles with bleomycin, etoposide, and cisplatin (BEP). There was no regular follow-up after her treatments at a local hospital, and AFP kept in normal level before her pregnancy. Twenty two months after her last cycle of chemotherapy (at her 21 weeks of gestation), the patient showed a right superior abdominal pain. Pathology report from her first surgery was “ovarian endodermal sinus tumor”. Magnetic resonance imaging (MRI) showed that there were several masses

A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer

Objectives To evaluate the feasibility, toxicity and activity of neoadjuvant chemotherapy (NACT) using cisplatin and topotecan in patients affected by locally advanced cervical cancer (IB2–IIIB). Methods Patients with histologically confirmed FIGO stage IB2–IIIB uterine cervical cancer were treated with topotecan 0.75 mg/m 2/day (days 1–3) followed by cisplatin 75 mg/m 2 (day 1), every 21 days for three consecutive cycles. After the last cycle of chemotherapy, within 3 or 4 weeks, patients underwent radical surgery with lymph node dissection. Results In the years 2007–2010, 46 women were enrolled into the study. Hematologic toxicity was the most relevant side effect. Thirty-eight patients (82.6%) underwent radical surgery after neoadjuvant chemotherapy (NACT ) and were assessable for pathologic responses; surgery was not performed in 8 (17.4%) non-responder patients or with progression disease. Objective pathological response was recorded in 34 patients (89.5%); 6 patients (15.8%) achieved a complete response (CR ), 28 (73.7%) patients achieved a partial response (PR); stable disease (SD) occurred in 2 patients (5.3%) with IIA initial disease and progression disease (PD) was registered in 2 patients (5.3%) with IIIB initial disease. The cumulative 2-year progression free survival (PFS ) and overall survival (OS) of the 46 enrolled patients in the study were 70% and 81%, respectively; the 2-year PFS and OS of the 38 operated patients were respectively 79% and 95%. Conclusions The cisplatin–topotecan combination seems to be feasible and with an acceptable toxicity profile and a promising response rate for the treatment of locally advanced cervical cancer (LACC). Phase II and III studies are needed to compare this combination with other platinum-based chemotherapeutic associations.

Development of Acute Megakaryoblastic Leukemia with Isochromosome (12p) after a Primary Mediastinal Germ Cell Tumor in Korea

The association of hematological malignancies with a mediastinal germ cell tumor (GCT) is very rare. We report one case of a young adult male with primary mediastinal GCT who subsequently developed acute megakaryoblastic leukemia involving isochromosome (12p). A 25-yr-old man had been diagnosed with a mediastinal GCT and underwent surgical resection and adjuvant chemotherapy. At 1 week after the last cycle of chemotherapy, his peripheral blood showed leukocytosis with blasts. A bone marrow study confirmed the acute megakaryoblastic leukemia. A cytogenetic study revealed a complex karyotype with i(12p). Although additional chemotherapy was administered, the patient could not attain remission and died of septic shock. This case was definitely distinct from therapy-related secondary leukemia in terms of clinical, morphologic, and cytogenetic features. To our knowledge, this is the first case report of a patient with mediastinal GCT subsequently developing acute megakaryoblastic leukemia involving i(12p) in Korea.

Low Bone Mineral Density and High Bone Turnover In Patients with Non-Hodgkin's Lymphoma (NHL) Who Receive Frontline Therapy: Results of a Multicenter Prospective Study

AbstractAbstract 5071Chemotherapy-associated bone loss is a severe problem in patients with malignancies as it increases the risk for fractures and deteriorates quality of life. However, there are very limited reports in the literature describing the effects of chemotherapy on bone metabolism of adult patients with NHL. To elucidate this issue we scheduled a prospective study in which patients with newly-diagnosed non-Hodgkin's lymphoma (NHL) had a thorough evaluation of bone remodeling, pre- and post- frontline chemotherapy. As of June 2009, 53 patients (33M/20F, median age 59 years, range: 18–90 years) had completed their first-line treatment: 36 patients (67.9%) had diffuse large B-cell lymphoma, 5 (9.4%) follicular lymphoma (grade III), 4 (7.5%) mantle-cell lymphoma, 6 (11.3%) marginal-zone lymphoma and 2 (3.8%) T-cell NHL. Nineteen patients (35.8%) had stage IV disease and B-symptoms before therapy initiation. Forty-seven patients (88.7%) received R-CHOP (40 every 21 days and 7 every 14 days), 4 received R-COP and 2 received CHOP as first-line therapy for their disease. Bone mineral density (BMD) of the lumbar spine (L1-L4, antero-posterior view), and femoral neck (FN) was measured by dual energy X-ray absorptiometry (DXA) on day 1 of cycle 1 (baseline) and on day 30 of the last cycle of chemotherapy. The following serum indices of bone metabolism were measured on the days of DXA: i) osteoclast stimulators [sRANKL and osteoprotegerin (OPG)], ii) osteoblast regulators [parathyroid hormone, vitamin-D, and dickkopf-1 (Dkk-1)], iii) bone resorption markers [C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase-5b (TRACP-5b)], and iv) bone formation markers [bone alkaline phosphatase (bALP) and osteocalcin (OC)]. The above markers were also evaluated in 30 healthy controls of similar gender and age. Patients were assessed for skeletal-related events (SREs) throughout the period of the study. At baseline, NHL patients had a median T-score of L1-L4 BMD of -0.63 (range -4.27 to +3.68) and of FN BMD of -0.875 (-4.01 to +2.07). The median T-score of the lumbar vertebra with the major bone loss was -1.425 (-4.6 to +3.03). At baseline patients had reduced levels of OC (p=0.01) compared to controls, while CTX, TRACP-5b and sRANKL/OPG ratio did not differ between patients and controls. There was a strong correlation between L1-L4 and FN BMD (r=0.64, p<0.0001) as well as between CTX with TRACP-5b (r=0.467, p=0.001), sRANKL (r=0.479, p=0.001) and Dkk-1 (r=0.442, p=0.003). Strong correlations were also observed between bALP and sRANKL/OPG ratio (r=0.406, p=0.006), Dkk-1 and TRACP-5b, (r=0.421, p=0.004), sRANKL and CTX (r=0.479, p=0.001). There was no correlation between BMD and NHL stage. The administration of chemotherapy resulted in a dramatic reduction of BMD in L1-L4 (median T-score: -1.12; range -4.49 to +3.04; p<0.001 and median T-score of the lumbar vertebra with the major loss: -1.45; range: -4.84 to +2.72; p=0.001) and in FN BMD (median T-score: -1.115; range: -3.68 to +1.12; p<0.001) compared to baseline values. The reduction of L1-L4 and FN BMD post-chemotherapy was more profound in males (p=0.003 and p=0.001 respectively) than in females (p=0.011 and p=0.01) and in patients of >55 years (p=0.001 and p<0.001 respectively) compared to all others (p=0.037 and p=0.014). This reduction was irrespective of the NHL stage (I/II vs. III/IV), while patients who received 8 cycles of chemotherapy had a greater reduction of L1-L4 (p<0.001) and FN (p=0.001) BMD compared to all others. The administration of chemotherapy also resulted in a dramatic increase of CTX (p=0.017), TRACP-5b (p<0.001), bALP (p<0.001), OC (p<0.001) and Dkk-1 (p=0.022) compared to baseline values. All studied markers of bone remodeling, with the exception of OPG and sRANKL, were significantly increased in NHL patients post-chemotherapy compared to controls (p=0.05 for CTX, p<0.001 for TRACP-5b and Dkk-1, p=0.01 for bALP, p=0.015 for OC). During study period, one male patient had a pathological fracture in his right FN. We conclude that frontline treatment with the combination of chemotherapy and/or rituximab results in high bone turnover, which leads to increased bone loss and reduced BMD of L1-L4 and FN in NHL patients. The prophylactic use of anti-resorptive agents, such as bisphosphonates, or the administration of agents with anti-Dkk-1 activity may be useful for preventing bone loss in these patients. Disclosures:No relevant conflicts of interest to declare.

Consequences of Chemotherapy Induced Myelosuppression In Patients with Chronic Lymphocytic Leukemia (CLL)

AbstractAbstract 4637Purine analogs, including fludarabine and pentostatin, are frequently used as first-line agents once therapy of CLL commences. However, as a result of such treatment, approximately 20% of patients become myelosuppressed to the extent that a full course of therapy cannot be given. Myelosuppression was defined as absolute neutrophil count < 1500/uL and/or platelets < 100,000 for two consecutive laboratory findings, occurring anytime from the initiation of purine analog chemotherapy until one month following last cycle of chemotherapy. We sought to determine the consequences of such myelosuppression by retrospective analysis of all patients with CLL undergoing initial treatment that included purine analogs between 2003 and 2008 at the Cleveland Clinic. We identified 45 patients meeting these criteria. The median age at treatment was 63 (range 41 to 82) and all met standard criteria for the diagnosis and treatment of CLL. Of these 45 patients, 19 could not complete all 6 cycles of planned treatment. Of these 45 patients, 9 (20% of the 45 patients analyzed) could not complete treatment due to persisting myelosuppression. The clinical characteristics of these 9 patients are compared to the other 36 patients in the table.We attempted to correlate CD38 and Zap-70 expression with pre-treatment risk factors (age, Rai stage, and performance status), but found no association, except in the case of CD38 positivity in relation to PS ≥ 1 (p = 0.04). Cytogenetics were unknown for a majority of patients and therefore were not analyzed. The 9 patients remained myelosuppressed for a median of 10 months (range 2 to 41), and 6 of these 9 patients were platelet transfusion dependent at some point (compared to 1 of 36 patients of the non-myelosuppressed group, p <0.001). Of the 9 myelosuppressed patients, 6 recovered hematopoiesis after a median of 11 months (range 7–41), 4 relapsed with CLL after a median of 29 months (range 12 – 51), and 4 died. Of the 4 who died, 2 died while remaining myelosuppressed. Our data corroborates the findings of others that approximately 20% of patients treated with purine analogs will experience enough myelosuppression to reduce the number of cycles that can be delivered. Although we could not identify many significant pre-treatment predictors of such myelosuppression, we did observe that some patients remained myelosuppressed for long periods of time, often with adverse consequences, including transfusion dependence, relapse, and death. Efforts to avoid prolonged myelosuppression by better patient selection and strict attention to recommendations for dose reductions, rather than dose delays, may lessen the incidence of such consequences. Disclosures:Kalaycio:Genzyme: Speakers Bureau; Genetech: Speakers Bureau; Cephalon: Speakers Bureau.

High-dose therapy followed by autologous stem-cell transplantation with and without rituximab for primary treatment of high-risk diffuse large B-cell lymphoma

BackgroundWe aimed to determine safety and efficacy of rituximab (R) in combination with repetitive high-dose therapy (HDT) as primary treatment for diffuse large B-cell lymphoma (DLBCL). Patients and methodsPatients aged 18–60 years and elevated lactate dehydrogenase were treated with four cycles of MegaCHOEP and transplantation of autologous stem cells after cycles 2, 3 and 4. Rituximab (375 mg/m2) was given before each cycle and 12 and 33 days after start of the last cycle of chemotherapy. Sixty-four patients given R-MegaCHOEP were compared with 29 patients who had received identical treatment without rituximab. ResultsOverall survival (OS) and event-free survival (EFS) after 3 years were significantly improved in patients treated with R-MegaCHOEP (OS: 78.7% versus 55.0%, P = 0.045; EFS: 72.7% versus 47.2%, P = 0.013). In a Cox regression model adjusted for performance status and stage, relative risk of treatment failure was lower (relative risk 0.5, P = 0.041) and OS was better (relative risk 0.4, P = 0.054) for patients given R-MegaCHOEP. Grade 3/4 infections were more frequent in the R-MegaCHOEP group (18.5% versus 6.0%, P = 0.003). ConclusionsThe addition of rituximab to MegaCHOEP significantly improved outcome in young patients with high-risk DLBCL. The higher incidence of grade 3/4 infections needs consideration when rituximab and HDT regimens are combined.

Prognostic analysis of acute exacerbations of hepatitis-B after chemotherapy in combination with rituximab in 19 patients with lymphoma

The prognosis and management of acute exacerbations of hepatitis-B in patients with lymphoma after chemotherapy in combination with rituximab remain unclear. Here, we describe 19 Chinese patients with lymphoma who suffered this complication, in order to analyze their clinical characteristics. Receiver operating characteristic analysis and Kaplan–Meier survival analysis were utilized to determine potential prognostic factors. We found that key prognostic factors included the peak prothrombin time (PT), international normalized ratio (INR), and total bilirubin (TB), as well as the PT and INR on admission and the interval between acute exacerbation of hepatitis-B and the last cycle of chemotherapy. Moreover, our data suggested that shorter interval between the last cycle of rituximab and acute exacerbation of hepatitis-B might be another prognostic indicator of inferior survival. Our results revealed that the severity of hepatic damage and the interval between the last cycle of chemotherapy and hepatitis flare were the major prognostic factors of an acute exacerbation of hepatitis-B induced by immunochemotherapy. Prophylactic antiviral and rescue antiviral therapy remain to be further characterized.

Interval from neoadjuvant chemotherapy to interval debulking surgery in advanced ovarian cancer: Is this a prognostic indicator?

5084 Background: We hypothesized that longer interval between neoadjuvant chemotherapy and interval debulking surgery (IDS) may have an adverse effect on survival. We analyzed the data of patients with advanced epithelial ovarian cancer to evaluate the effect of interval from last cycle of chemotherapy to interval debulking surgery (IDS) on progression free and overall survival. Methods: We retrospectively analyzed case records of 86 patients of advanced epithelial ovarian cancer (stage IIIC and IV) who received neoadjuvant chemotherapy and underwent IDS at our centre from Jan 2001 to Dec 2008. Data was obtained for age, stage of the disease, operative procedure, pathology, recurrence and survival. Response rate was compared using 2 sided chi square test. Progression free (PFS) and overall survival (OS) were analyzed using Kaplan Meier technique with log rank test. Hazard ratio was obtained by cox regression model. Results: Patients' median age was 50 years (range 32 to 75). 55 patients had stage IIIC and stage IV-31. A median of 3 chemotherapy cycles were administered prior to IDS (range, 3-7) and the median interval between last cycle of chemotherapy and IDS was 41 days (range 16-93 days). 67.5% patients had optimal debulking (residual disease ≤ 1 cm). 44 patients were operated within 42 days and 42 patients underwent surgery after 42 days. The response rate (complete + partial) was higher for patients operated within 42 days (40/44 vs. 30/42, p < 0.02). At a median follow up of 30 months- the median overall and PFS for whole group is 37 months (95% CI: 30-44) and 13 months (95% CI: 11-15), respectively. Both PFS and OS rates are significantly higher for patients operated within 42 days of last chemotherapy cycle; PFS: 18 vs. 9 months, p < 0.0001, HR-2.86 (95% CI:1.76-4.67) and OS: 45 vs. 27 months, p < 0.003, HR-2.19 (95% CI:1.27-3.79). Conclusions: This study indicates adverse outcome for patients who undergo interval debulking surgery more than 6 weeks after last cycle of neoadjuvant chemotherapy. No significant financial relationships to disclose.

Phase II study of combined docetaxel, epirubicin, and cyclophosphamide as a neoadjuvant chemotherapy regimen in patients with locally advanced breast cancer in a single institution.

e11040 Background: Neoadjuvant chemotherapy with anthracycline and taxane combinations is a standard approach for locally advanced breast cancer. One commonly used regimen is docetaxel, doxorubicin and cyclophosphamide. Epirubicin is another anthracycline used in breast cancer but the combined use of epirubicin and taxane is not well established. We conducted a single institution, phase II study to assess the efficacy of combined docetaxel, epirubicin and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen. Methods: Eligible patients were female with newly diagnosed locally advanced breast cancer defined as T2 > 3 cm, T3-4, any N, or any T, N1-3, M0. A chemotherapy regimen of docetaxel 75 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2 was given with growth factor support every 3 weeks for 6 cycles. All patients had surgery within 3-6 weeks after completion of chemotherapy. Primary end-point was pathologic complete response (pCR). Results: Twenty-one patients were registered from December 2003 to December 2006. One patient was excluded because of history of thyroid cancer. Median age was 51 (29-70). Eight patients (40%) were premenopausal. Ten patients (50%) had negative tumor hormone receptors. Four patients (20%) who had HER2/neu overexpression received adjuvant trastuzumab. All but one patient completed 6 cycles of TEC chemotherapy. One patient refused to receive the last cycle of chemotherapy. Fourteen patients (70%) had lumpectomy and 6 patients (30%) underwent mastectomy. The pCR rate was 25%. Eight of 16 patients with N1-3 disease (50%) had pathological negative lymph nodes. With a median follow up of 57.5 (16-71) months, 4 patients (20%) relapsed with 1 died from recurrence. The estimated 5-year relapse free survival is 79%. No patient had cardiac failure or death during treatment. The most common grade 3-4 toxicity was neutropenia (35%). Conclusions: Combined TEC regimen is a feasible, well-tolerated and effective neoadjuvant chemotherapy regimen for locally advanced breast cancer that results in a pCR rate of 25%. No significant financial relationships to disclose.

Vitamin D deficiency and bone mineral density in postmenopausal women receiving aromatase inhibitors for early breast cancer

Objective Aromatase inhibitors (AI) treatment leads to an increased risk of bone loss and fractures. In a group of women with early breast cancer (EBC) and baseline Vitamin D deficiency (<30 ng/ml) who are treated with AI, we aim to describe: serum levels of Vitamin D, bone mineral density (BMD), calcium intake, and the increase of serum 25(OH)D accomplished in 3 months of treatment with Vitamin D supplements. Study design Prospective, non-randomized clinical trial. Methods In 232 consecutively included women with EBC in treatment with AI, we assessed baseline calcium intake, serum levels of 25(OH)D, BMD and, spine X-ray. All received Calcium and Vitamin D supplements, and those with vitamin deficiency received 16,000 IU Vitamin D every 2 weeks. Serum levels of 25(OH)D were newly assessed after treatment. All the baseline evaluation was performed before starting AI treatment. Results Mean age at baseline (±SD) was 63.2 ± 8.8 years. In 150 (64.9%) cases, the women had been treated previously with tamoxifen; 101 (43.7%) started exemestane, 119 (51.5%) letrozole, and 11 (4.8%) anastrozole. The AI were initiated within 6 weeks after surgery or after the last cycle of chemotherapy. At baseline, 88.1% had 25(OH)D levels <30 ng/ml, 21.2% had severe deficiency (<10 ng/ml), and 25% of the participants had osteoporosis. Mean daily calcium intake was low (841 ± 338). We found a significant association between 25(OH)D levels and BMD at baseline, which remained significant in femoral neck BMD after multivariate adjustment. Plasma 25(OH)D levels improved significantly at 3 months follow-up in those treated with high dose Vitamin D supplements: mean increase 32.55 ng/ml (95%CI 28.06–37.03). Conclusions Our study suggests a high prevalence of commonly unrecognized Vitamin D deficiency in women with EBC treated with AI, a known osteopenic agent. Our results support the need for a routine assessment of 25(OH)D levels and, when necessary, supplementation in these patients.