Nephrotoxicity of cisplatin combination chemotherapy in thoracic malignancy patients with CKD risk factors.

BACKGROUND: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI. METHODS: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25% from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or ≥ 1.5 times the baseline level. RESULTS: Eighty of the 84 patients (95.2%) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4%). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95% confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95% CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI. CONCLUSIONS: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use.

The role of glutamine supplementation in thoracic and upper aerodigestive malignancies.

In cancer patients, marked glutamine (gln) depletion develops over time. Host tissues (epithelial cells and lymphocytes) that depend upon adequate stores of gln for optimal functioning can be negatively influenced. In addition, radiation and/or chemotherapy cause normal tissues damage that might be enhanced by this depletion effect. The present review evaluates in vivo clinical data about the potential beneficial role of gln administration in the prevention of host tissue toxicity, in a patient group with thoracic and upper aerodigestive malignancies (T&UAM) during cancer treatment. Publications were identified in a systematic review of MEDLINE Database from the last 2 decades (1994-2014) using key search terms and through manual searches. Overall, 13 clinical studies (9 oral/4 parenteral) evaluated the safety and tolerance of gln supply, showing a beneficial effect in the grade, duration of mucositis and esophagitis, decreased gut permeability, and weight loss. Only 1 Phase 1 clinical trial had negative results because the chemo-radiotherapy combined treatment was not feasible. The use of oral gln may especially have an important role in the prevention of acute radiation toxicities, the weight loss and the need for analgesics in patients with T&UAM, especially if the treatment plan includes combined modality therapy with chemo-radiation.

Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy.

BACKGROUND AND PURPOSE: Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence. METHODS: Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45 Gy). Patients were followed up every 1.5-3 months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0. RESULTS: Twenty-three (85%) patients were previously irradiated (median 60.4 Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11 months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1 year LPFS was 76%. Overall survival was 23 months for patients with CR, and 5.4 months in patients achieving a partial response (PR) (p=0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures. CONCLUSIONS: ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.

Retrospective review of cancer patients > or =80 years old treated with chemotherapy at a comprehensive cancer center.

CONTEXT: The percentage of cancer patients > or =80 years old is expected to increase in the next few years. However data on the use of chemotherapy in these patients are limited. OBJECTIVE: We conducted a retrospective review to define the profile of patients > or =80 years old who received chemotherapy at our center and assess their survival. DESIGN, SETTING AND PARTICIPANTS: Patients > or =80 years treated with chemotherapy between 1 January 2000 and 31 December 2004 were included in this analysis. RESULTS: Of the 4689 patients treated with chemotherapy over the 5-year period, 133 patients (3%) were > or =80 years old. The median age was 83 years. 61% were females and 39% were males. 16% had hematologic tumors and 84% had solid tumors. Gynecological (32%) and aerodigestive cancers (27%) were the most common sites and lung cancer (22%) was the most common cancer. During the first regimen, 512 cycles of chemotherapy were delivered with a median of 3 cycles (range: 1-24 cycles). 49% received single and 51% multidrug regimens. Carboplatin was the most common single agent and carboplatin and paclitaxel was the most common combination among solid tumor patients. 19% of solid tumor patients received radiation with chemotherapy. The 1-year survival among hematologic cancer and solid tumor patients was 65% and 48%, respectively. Stage of disease was the only statistically significant factor predicting survival. CONCLUSIONS: In cancer patients > or =80 years old selected for chemotherapy, both single and multi-agent therapy appeared to be feasible.

Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation.

Inhibitors of histone deacetylases have been shown to enhance the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL-mediated cytotoxicity in cultured thoracic cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured thoracic cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5-5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combination, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic for thoracic cancers.

Combined administration of ethodolac, ascorbic acid and radiotherapy as adjuvant therapies in an extrathoracic desmoid tumor with gross postoperative residual disease; case report and review of the literature.

A 37-year-old man was admitted with an extrathoracic desmoid tumor invading the brachial plexus. Magnetic resonance imaging (MRI) of the thorax demonstrated a 20 x 9 x 14 cm mass in the supraclavicular fossa, axillary fossa and the right side of the chest. It invaded the brachial plexus and circumscribed the subclavian and axillary arteries concentrically. Biopsy revealed desmoid tumor which was resected subtotally with the brachial plexus. The gross residual mass was treated postoperatively with radiotherapy (60 Gy) which resulted in major regression of the mass. Following radiotherapy, ethodolac with ascorbic acid were administered. The tumor was clinically indiscernible 35 months post-radiotherapy. This case shows the high effectiveness of radiotherapy along with less toxic medical treatment modalities in instances where local control is hard to achieve with surgery and highlights the importance of using multidisciplinary treatments to maintain good functional results.

[A case of postoperative chestwall recurrence of gastric cancer responding to a combination of radiation, hyperthermia and oral administration of TS-1].

A 77-year-old man diagnosed with advanced gastric cancer underwent total gastrectomy with combined splenectomy and resection of the pancreatic tails in 1996. He was treated with 400 mg/day of UFT for 2 years. Serum CEA level was found to be elevated on July 5, 2001. He complained of left chest pain in December 2001. A 4 cm-sized tumor was detected in the region extending from the subcutaneous region to the left chest wall containing the osteolytic change of the left sixth rib. He was diagnosed with a chest wall metastasis from gastric cancer. He underwent radiotherapy with thermotherapy and was also treated with chemotherapy. TS-1 was administered at 80-100 mg/body/day, twice daily for 3 weeks followed by a 2-week rest interval as 1 cycle. As a results, shrinkage of the tumor was confirmed on February 14, 2002. The tumor was confirmed to have disappeared on April 17, 2002, by chest CT. A complete response of the metastatic tumor was achieved. The patient maintained a complete response for more than 12 months, but died from the chest wall metastasis recurrence and weakness on August 13, 2003. The only observed adverse event, was grade 2 leukopenia.

Pemetrexed and its emerging role in the treatment of thoracic malignancies.

Pemetrexed (Alimta); Eli Lilly and Co., Indianapolis, IN, USA) is a unique multitargeted antifolate that inhibits at least three enzymes, thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. This novel drug is being evaluated in a comprehensive clinical programme for use in both front-line and second-line therapies. It has shown broad activity in a number of solid tumours, including colon cancer, breast cancer, lung cancer, head and neck, cervical cancer and others. While a number of antifolates have been evaluated in clinical trials, further development has been stopped or delayed by the occurrence of life-threatening toxicities. Similar trends were also initially observed with pemetrexed as well, but investigators later showed that these toxicities could be minimised with folic acid and vitamin B(12) supplementation included in the treatment regimen. Preliminary data indicate that this supplementation does not hamper drug efficacy in most tumour types and in many cases, supplemented patients exhibit improved clinical outcome. Here, the current data for pemetrexed in treating thoracic malignancies are reviewed, with special focus on malignant pleural mesothelioma and non-small cell lung cancer.

A phase I trial of concomitant chemoradiotherapy with cisplatin dose intensification and granulocyte-colony stimulating factor support for advanced malignancies of the chest.

UNLABELLED: Concomitant chemoradiotherapy with cisplatin and combination chemotherapy in the neoadjuvant setting have both shown promising results. PURPOSE: To identify a locally and systemically active concomitant chemoradiotherapy regimen incorporating high-dose cisplatin, interferon alfa-2a (IFN), fluorouracil (5-FU), hydroxyurea (HU) and radiotherapy. METHODS: Phase I cohort design establishing the maximal tolerated dose (MTD) of cisplatin with and without granulocyte colony stimulating factor (GCSF). For the first six dose levels, a 4-week cycle consisted of escalating doses of cisplatin during weeks 1 and 2, IFN (week 1), and 5-FU and HU (week 2) with single daily radiation fractions of 200 cGy during days 1-5 of weeks 1-3 and no treatment in week 4. When dose-limiting neutropenia was encountered. GCSF was added during weeks 1, 3, and 4. Finally, to decrease esophagitis, the radiotherapy schedule was altered to 150 cGy twice daily during weeks 1 and 2, followed by a 2-week break (level 7). RESULTS: Forty-nine patients with refractory chest malignancies were treated. The MTD of this regimen without GCSF was cisplatin 50 mg/m2 in weeks 1 and 2, IFN 5 million Units (MU)/m2 per day on days 1-5 in week 1, 5-FU 800 mg/m2 per day for 5 days by continuous infusion, and HU 500 mg every 12 h for 11 doses during week 2. The addition of GCSF during weeks 1, 3, and 4 allowed for escalation of cisplatin to 100 mg/m2 during weeks 1 and 2, with a decreased dose of IFN at 2.5 MU/m2 per day to avoid renal toxicity. Dose-limiting toxicity (DLT) included severe neutropenia, thrombocytopenia, and esophagitis in 5 of 13 patients. Increased thrombocytopenia in patients receiving GCSF was not observed. During hyperfractionated radiotherapy (level 7) chemotherapy doses were as above except for a reduction of 5-FU to 600 mg/m2 per day. While severe esophagitis was reduced, grade 4 thrombocytopenia became more prevalent and was seen in 6 of 7 patients. In-field tumor responses were observed in 17 of 28 evaluated patients with non-small-cell lung cancer. The median times to progression and survival were 4 and 6 months, respectively. When only patients with all known disease confined to the radiotherapy field were considered the corresponding times were 6 and 15 months, respectively. Most treatment failures occurred outside of the irradiated field. CONCLUSIONS: (1) This intensive multimodality regimen can be given with aggressive supportive care incorporating GCSF. The recommended phase II doses for a 4-week cycle are cisplatin 50 mg/m2 week 1, and 100 mg/m2 week 2, IFN 2.5 MU, HU 500 mg every 12 h x 11 and 5-FU 800 mg/m2 per day with single fraction radiotherapy during weeks 1-3 and GCSF during weeks 1, 3, and 4. (2) GCSF can be safely administered and provides effective support of neutrophils when administered simultaneously with IFN, cisplatin, and chest radiotherapy. (3) There is synergistic renal toxicity when high doses of IFN and cisplatin are given together. (4) Hyperfractionated radiotherapy decreases the severity of esophagitis but increases thrombocytopenia. (5) Although highly toxic, response rates, time to progression and survival figures with this regimen are encouraging and support its investigation in the phase II setting.

Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age.

PURPOSE: To test the efficacy of a protocol for poor-risk neuroblastoma that builds on the following: (1) our favorable previously reported results with dose-intensive use of cyclophosphamide; (2) our retrospective analysis of neuroblastoma chemotherapy reports, which supported the value of high-dose cisplatin and etoposide (VP-16); and (3) the Goldie-Coldman hypothesis that rapid cytoreduction plus the use of non-cross-resistant chemotherapy combinations will decrease the risk of drug resistance. PATIENTS AND METHODS: The N6 protocol included seven courses of high-dose chemotherapy plus surgical resection of bulk disease. Courses 1, 2, 4, and 6 consisted of 6-hour intravenous infusions of cyclophosphamide 70 mg/kg/d on days 1 and 2 (ie, 140 mg/kg per course), a 72-hour intravenous infusion of doxorubicin 75 mg/m2 and vincristine 0.1 mg/kg beginning day 1, and vincristine 1.5 mg/m2 intravenous bolus on day 9. Courses 3, 5, and 7 consisted of 2-hour intravenous infusions of VP-16 200 mg/m2/d on days 1 to 3 (ie, 600 mg/m2 per course), and 1-hour intravenous infusions of cisplatin 50 mg/m2/d on days 1 to 4 (ie, 200 mg/m2 per course). Courses were to start after neutrophil counts reached 500/microL and platelet counts reached 100,000/microL. Response was defined by international criteria. RESULTS: Among 24 consecutive previously untreated patients diagnosed with stage 4 neuroblastoma at more than 1 year of age, 21 patients achieved a complete or very good partial remission; one patient had no evidence of disease except by iodine-131-metaiodobenzylguanidine (MIBG) scan, which was markedly improved; and one patient had resolution of extensive metastatic disease, but still had an incompletely resected primary tumor. The sole patient to have a poor response had clinical features at diagnosis that are atypical for neuroblastoma, namely, 8 years of age and an unknown primary tumor. Severe toxicities included myelosuppression, mucositis, and hearing deficits. CONCLUSION: The N6 approach reliably achieves significant cytoreduction against stage 4 neuroblastoma. This may eventuate in an improved cure rate, since consolidative treatments using myeloablative therapy, immunotherapy, or biologic response modifiers such as cis-retinoic acid are most likely to be effective against minimal residual disease.

Indomethacin and ascorbate inhibit desmoid tumors.

Administration of indomethacin caused complete resolution of a desmoid tumor after a partial response to radiation. In another patient, this drug caused an immediate response, then became ineffective. When large doses of ascorbic acid were given with indomethacin, slow resolution of the tumor began and has continued for 14 months. Treatment of a third case with indomethacin and ascorbic acid from the beginning produced shrinkage of the tumor which has continued to date.