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Between March 1985 and January 1987, 103 women with histologically proven stage III-IV ovarian carcinoma were randomly allocated to groups receiving monthly intravenous regimens of 1 g of cyclophosphamide/m plus either 60 mg of cisplatin (CDDP)/m or 150 mg of carboplatin (CBDCA)/m for 1 year unless disease progressed earlier. The groups were well balanced according to the stratification factors (age, histologic differentiation, extent of residual disease, and performance score), and both treatments were well tolerated and produced similar median first-course leukopenia (2,200 and 2,000 cells/μL) and thrombocytopenia (220,000 and 202,500 cellsμL). The CBDCA regimen was less emetogenic. After an interim analysis in January 1987 revealed superior progression-free survival for the group of 53 patients receiving CDDP ( =.005), the study was closed to further accrual. Those 24 patients still receiving CBDCA were encouraged to cross over to the CDDP-based regimen and 21 of them did. Following treatment crossover, the relative risk of death associated with original allocation to CBDCA receded from 1.79 to 0.97, indicating success of the salvage treatment using the CDDP-based regimen. This aborted study demonstrated the superiority of CDDP over CBDCA when the two platinum compounds were compared at equally myelosuppressive low doses in combination with 1 g of cyclophosphamide/m. If CDDP is to be supplanted by CBDCA, larger, more myelosuppressive doses of CBDCA will be required. The platinum drug antitumor effect is a critically important therapeutic feature of this combination. [J Natl Cancer Inst 81: 1500–1504, 1989] [ABSTRACT FROM PUBLISHER]

Chimeric antigen receptor (CAR) T cells have had limited success against solid tumors. Here, we used an oncolytic foamy virus (oFV) to display a model CAR target antigen (CD19) on tumors in combination with anti-CD19 CAR T cells. We generated oFV-Δ bel2 and oFV- bel2 vectors to test the efficiency and stability of viral/CD19 spread. While both viruses conferred equal CAR T killing in vitro , the oFV-Δ bel2 virus acquired G-to-A mutations, whereas oFV- bel2 virus had genome deletions. In subcutaneous tumor models in vivo , CAR T cells led to a significant decrease in oFV-specific bioluminescence, confirming clearance of oFV-infected tumor cells. However, the most effective therapy was with high-dose oFV in the absence of CAR T cells, indicating that CAR T clearance of oFV was detrimental. Moreover, in tumors that escaped CAR T cell treatment, resurgent virus contained deletions within the oFV-CD19 transgene, allowing the virus to escape CAR T elimination. Therefore, oFV represents a slow smoldering type of oncolytic virus, whose chronic spread through tumors generates anti-tumor therapy, which is abolished by CAR T therapy. These results suggest that further development of this oncolytic platform, with additional immunotherapeutic arming, may allow for an effective combination of chronic oncolysis., Competing Interests: R.V. was a recipient of a research grant from Vyriad Inc., (© 2024 The Author(s).)

Treatment of the most aggressive and deadliest form of skin cancer, the malignant melanoma, still has room for improvement. Its invasive nature and ability to rapidly metastasize and to develop resistance to standard treatment often result in a poor prognosis. While the highly effective standard chemotherapeutic agent doxorubicin (DOX) is widely used in a variety of cancers, systemic side effects still limit therapy. Especially, DOX-induced cardiotoxicity remains a big challenge. In contrast, the natural chalcone cardamonin (CD) has been shown to selectively kill tumor cells. Besides its anti-tumor activity, CD exhibits anti-oxidative, anti-inflammatory and anti-bacterial properties. In this study, we investigated the effect of the combinational treatment of DOX with CD on A375 melanoma cells compared to normal human dermal fibroblasts (NHDF) and rat cardiac myoblasts (H9C2 cells). DOX-induced cytotoxicity was unselective and affected all cell types, especially H9C2 cardiac myoblasts, demonstrating its cardiotoxic effect. In contrast, CD only decreased the cell viability of A375 melanoma cells, without harming normal (healthy) cells. The addition of CD selectively protected human dermal fibroblasts and rat cardiac myoblasts from DOX-induced cytotoxicity. While no apoptosis was induced by the combinational treatment in normal (healthy) cells, an apoptosis-mediated cytotoxicity was demonstrated in A375 melanoma cells. CD exhibited thiol reactivity as it was able to directly interact with N-acetylcysteine (NAC) in a cell-free assay and to induce heme oxygenase-1 (HO-1) in all cell types. And that took place in a reactive oxygen species (ROS)-independent manner. DOX decreased the mitochondrial membrane potential (Δψ m ) in all cell types, whereas CD selectively decreased mitochondrial respiration, affecting basal respiration, maximal respiration, spare respiratory capacity and ATP production in A375 melanoma cells, but not in healthy cardiac myoblasts. The DOX-induced cytotoxicity seen in melanoma cells was ROS-independent, whereas the cytotoxic effect of CD was associated with CD-induced ROS-formation and/or its thiol reactivity. This study highlights the beneficial properties of the addition of CD to DOX treatment, which might protect patients from DOX-induced cardiotoxicity. Future experiments with other tumor cell lines or a mouse model should substantiate this hypothesis.

Background: Malignant melanoma is the most aggressive form of skin cancer with a rather poor prognosis. Standard chemotherapy often results in severe side effects on normal (healthy) cells finally being difficult to tolerate for the patients. Shown by us earlier, cerium oxide nanoparticles (CNP, nanoceria) selectively killed A375 melanoma cells while not being cytotoxic at identical concentrations on non-cancerous cells. In conclusion, the redox-active CNP exhibited both prooxidative as well as antioxidative properties. In that context, CNP induced mitochondrial dysfunction in the studied melanoma cells via generation of reactive oxygene species (primarily hydrogen peroxide (H2O2)), but that does not account for 100% of the toxicity., Aim: Cancer cells often show an increased glycolytic rate (Warburg effect), therefore we focused on CNP mediated changes of the glucose metabolism., Results: It has been shown before that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity is regulated via oxidation of a cysteine in the active center of the enzyme with a subsequent loss of activity. Upon CNP treatment, formation of cellular lactate and GAPDH activity were significantly lowered. The treatment of melanoma cells and melanocytes with the GAPDH inhibitor heptelidic acid (HA) decreased viability to a much higher extent in the cancer cells than in the studied normal (healthy) cells, highlighting and supporting the important role of GAPDH in cancer cells., Conclusion: We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a target protein for CNP mediated thiol oxidation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 von Montfort et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neuroblastoma is the most common extracranial malignant tumor in childhood. Approximately 60% of all patients are classified as high-risk and require intensive treatment including non-selective chemotherapeutic agents leading to severe side effects. Recently, phytochemicals like the natural chalcone cardamonin (CD) have gained attention in cancer research. For the first time, we investigated the selective anti-cancer effects of CD in SH-SY5Y human neuroblastoma cells compared to healthy (normal) fibroblasts (NHDF). Our study revealed selective and dose-dependent cytotoxicity of CD in SH-SY5Y. The natural chalcone CD specifically altered the mitochondrial membrane potential (ΔΨm), as an early marker of apoptosis, in human neuroblastoma cells. Caspase activity was also selectively induced and the amount of cleaved caspase substrates such as PARP was thus increased in human neuroblastoma cells. CD-mediated apoptotic cell death was rescued by pan caspase inhibitor Z-VAD-FMK. The natural chalcone CD selectively induced apoptosis, the programmed cell death, in SH-SY5Y human neuroblastoma cells whereas NHDF being a model for normal (healthy) cells were unaffected. Our data indicates a clinical potential of CD in the more selective and less harmful treatment of neuroblastoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cutaneous basal and squamous cell carcinoma reflect the first and second most common type of non-melanoma skin cancer, respectively. Especially cutaneous squamous cell carcinoma has the tendency to metastasize, finally resulting in a rather poor prognosis. Therapeutic options comprise surgery, radiation therapy, and a systemic or targeted chemotherapy. There are some good treatment results, but overall, the response rate of newly developed drugs is still modest. Drug repurposing represents an alternative approach where already available and clinically approved substances are used, which originally intended for other clinical benefits. In this context, we tested the effect of the naturally occurring polyphenolic aldehyde (±) gossypol with concentrations between 1 and 5 µM on the invasive squamous cell carcinoma cell line SCL-1 and normal human epidermal keratinocytes. Gossypol treatment up to 96 h resulted in a selective cytotoxicity of SCL-1 cells (IC 50 : 1.7 µM, 96 h) compared with normal keratinocytes (IC 50 : ≥ 5.4 µM, 96 h) which is mediated by mitochondrial dysfunction and finally leading to necroptotic cell death. Taken together, gossypol shows a high potential as an alternative anticancer drug for the treatment of cutaneous squamous cell carcinoma., (© 2023. The Author(s).)

Background: Medulloblastoma (MB) is the most common malignant primary brain tumor of childhood. High risk patients still have a poor outcome, and especially young patients suffer from standard therapy induced sequelae. Therefore, other therapeutic options need to be explored. In glioblastoma (GBM), application of 5-aminolaevulinic acid (5-ALA) results in selective accumulation of protoporphyrin IX (PPIX) in the tumor cells, which can be exploited during fluorescence-guided surgery to increase the extent of resection or for photodynamic therapy (PDT) induced phototoxicity. It is not entirely clear, whether MB cells accumulate PPIX and are sensitive to PDT., Methods: Human MYC-amplified (Med8A and D283) and non-amplified (UW228-2 and ONS76) MB cell lines were incubated for 2, 4 or 6 h with increasing doses (0-100 μg/ml) of 5-ALA, and PPIX accumulation was determined by flow cytometry. To assess sensitivity to 5-ALA/PDT, cells were incubated with 5-ALA and subsequently exposed to laser light of 635 nm wavelength (18.75 J/cm 2 ). After an additional 24 h culture period, viability of cells was quantified using the WST-1 assay. Expression of ferrochelatase was detected by reverse transcription and quantitative polymerase chain reaction. Ferrochelatase activity was quantified by measuring the enzymatic conversion of PPIX to zinc-protoporphyrin. Expression of the ABCG2 transporter protein CD338 was detected by flow cytometry., Results: All MB cell lines showed a time- and dose-dependent accumulation of PPIX after exposure to exogenous 5-ALA and became sensitive to 5-ALA/PDT-induced phototoxicity. PPIX accumulation was reduced compared to U373 GBM cells at shorter incubation periods and limiting 5-ALA doses. Moreover, not all MB cells became PPIX positive and overall phototoxicity was lower in the MB cell lines. Notably, the MYC-amplified MB cells demonstrated a more pronounced photosensitivity compared to their non-amplified counterparts. There was no difference in expression of ferrochelatase, but enzymatic activity appeared to be reduced in the MB cells compared to U373 GBM cells, whereas CD338 was expressed on the MB cells only., Conclusion: Medulloblastoma cell lines accumulate PPIX after application of 5-ALA and become sensitive to PDT, associated with low ferrochelatase expression and activity. Photosensitivity is more pronounced in MYC-amplified cell lines. In contrast to GBM cells, however, PPIX accumulation appears to be reduced, restricted to a subset of cells and associated with lower photosensitivity of the MB cell lines, possibly due to expression of the ABCG2 transporter protein CD338 on MB cells., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chordomas are very rare tumors of the skull base and the sacrum. They show infiltrating and destructive growth and are known to be chemo- and radio-resistant. After surgical resection, the recurrence rate is high and overall survival limited. As current adjuvant treatments are ineffective, new treatment concepts are urgently needed. 5-aminolevulinic acid-based photodynamic therapy (5-ALA based PDT) showed promising results for malignant gliomas. However, it is unknown so far, whether chordomas accumulate protoporphyrin IX (PPIX) after application of 5-ALA and whether they are sensitive to subsequent 5-ALA based PDT., Methods: The immortalized human chordoma cells U-CH2 were used as in vitro model. After incubation for 4h or 6h with different 5-ALA concentrations, PPIX accumulation was determined by flow cytometry. To assess sensitivity to PDT, chordoma cells were incubated at 30.000cells/well (high cell density) or 15.000cells/well (low cell density) with graded doses of 5-ALA (0-50μg/ml) in 96-well plates and subsequently exposed to laser light of 635nm wavelength (18.75J/cm 2 ). Cell survival was measured 24h after exposure to laser light using the WST-1 assay., Results: U-CH2 cells dose-dependently accumulated PPIX (ANOVA; p<0.0001). PPIX fluorescence was significantly higher, when cells were incubated with 5-ALA for 6h compared to 4h at higher 5-ALA concentrations (ANOVA/Bonferroni; p≤0.05 for≥30μg/ml 5-ALA). For both cell densities, a 5-ALA dose-dependent decline in viability was observed (ANOVA; p<0.0001). Viability was significantly lower at higher 5-ALA concentrations, when 30.000 cells/wells were treated compared to 15.000cells/well (ANOVA/Bonferroni; p≤0.001 for≥30μg/ml 5-ALA). LD50 was 30.25μg/ml 5-ALA., Conclusion: The human UCH-2 cell line was a very useful in vitro model to study different effects of 5-ALA based PDT. For the first time, it could be shown that human chordoma cells may be destroyed by 5-ALA/PDT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) is the most frequent and lethal primary brain tumor in adults. Despite multimodal therapy combining resection, radio- and alkylating chemotherapy, disease recurrence is universal and prognosis of patients is poor. Glioblastoma stem-like cells (GSC), which can be grown as neurospheres from primary tumors in vitro, appear to be resistant to the established therapies and are suspected to be the driving force for disease recurrence. Thus, efficacy of emerging therapies may depend on targeting GSC. 5-aminolaevulinic acid-mediated photodynamic therapy (5-ALA/PDT) is a promising therapeutic approach in GBM. It utilizes the selective accumulation of the photosensitizer protoporphyrin IX (PPIX) in GBM cells after application of 5-ALA. When exposed to laser light of 635nm wavelength, PPIX initiates a photochemical reaction resulting in the generation of reactive oxygen species, which kill the tumor cells. Whether GSC accumulate PPIX and are sensitive to 5-ALA/PDT is currently unknown. Therefore, human GSC were derived from primary tumors and grown as neurospheres under serum free conditions. When subjected to exogenous 5-ALA, a dose- and time-dependent accumulation of PPIX in GSC was observed by flow cytometry, which varied between individual GSC preparations. Subsequent exposure to laser light of 635nm wavelength substantially killed GSC, whereas treatment with 5-ALA or exposure to laser light only had no effect. LD50 values differed between GSC preparations, but were negatively correlated with PPIX accumulation in GSC. In summary, we report for the first time that glioblastoma stem-like cells accumulate PPIX when subjected to 5-aminolaevulinic acid and are sensitive to 5-aminolaevulinc acid based photodynamic therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: The evaluation of drug disposition properties of chemical entities in drug discovery research typically involves the conduct of pharmacokinetic studies in rodents that requires blood sampling over several time points, preferably without disrupting the physiological status of the animals. Several blood withdrawal methods have been employed throughout the industry, yet these methods have not been comprehensively evaluated with regard to their effects on pharmacokinetic profiles of the drug investigated to recommend best practices., Methods: In this paper, the pharmacokinetics of six marketed drugs from four distinct therapeutic classes were compared using tail-vein, femoral-artery cannula-, and retro-orbital sinus bleeding techniques. The marketed drugs used in these studies were pentoxifylline, gemfibrozil, glipizide, methotrexate, clonidine, and fluoxetine., Results: Following oral administration, peak plasma concentration (C(max)), and area under the curve (AUC(0-24)) values for all compounds were not significantly different with the tail-vein method when compared to cannula- or retro-orbital sinus bleeding, except for fluoxetine and gemfibrozil for which minor, but statistically significant differences were observed. The effect of arterial versus venous tail-bleeding on the pharmacokinetics of pentoxifylline indicated no statistical differences in either C(max) or AUC(0-24) values. However, for fluoxetine, higher exposures were observed with tail arterial than venous sampling (2-fold with respect to C(max) and 1.7-fold with respect to AUC(0-24), p<0.05)., Discussion: The observed differences with fluoxetine may be due to its pharmacological effects on thermoregulatory responses that influence tail blood flow, a hypothesis that remains to be tested. Based on these observations, we recommend the tail-bleeding technique for pharmacology or toxicology exposure and F% studies, particularly in early discovery work. Retro-orbital bleeding is controversial and is no longer considered a humane method. Cannula-bleeding, especially coupled with automated blood-collection techniques, has become the most efficient way for pharmaceutical industry to perform rat bioavailability studies.

At present there is no established standard chemotherapy for advanced gastric cancer. Combination regimens have yielded response rates at times exceeding 50% but with no improvement in survival compared to single agents. This study examined the role of 5-fluorouracil and high-dose levamisole in a phase II setting using survival as the main endpoint. Patients with advanced carcinomas of the stomach or gastroesophageal junction were treated with 5-fluorouracil, 450 mg/m2 IV days 1 to 5, and levamisole, 100 mg/m2 orally three times daily on days 1 to 3, and 50 mg/m2 tid days 4 to 5 every 5 weeks. To allow more rapid accrual and to study a population that more accurately reflects the makeup of patients treated in clinical practice, patients with both measurable and nonmeasurable disease were entered in this study. Two of fifteen (13%) patients with measurable disease experienced a partial response to treatment. The adjusted 1-year survival rate for the 44 patients entered was 29.6%, which is similar to the historical 1-year survival of 30% observed in a group of nearly 400 patients treated in prior North Central Cancer Treatment Group studies. This regimen offers no improvement in therapeutic activity for advanced gastric cancer. This study design, however, allows rapid screening of phase II regimens in patients who would usually be candidates for phase III trials.

Mucositis is a prominent dose-limiting toxicity associated with 5-FU-based chemotherapy. On the basis of preliminary data suggesting that the amino acid glutamine could alleviate this problem, the authors developed this trial. Patients scheduled to receive their first 5-FU-based chemotherapy regimen were selected for study. Following stratification, patients were randomized, in a double-blind manner, to receive oral glutamine or a placebo preparation in a prophylactic manner. Patients in both groups were given oral cryotherapy before chemotherapy and were evaluated for mucositis by standard physicians' evaluation and by a self-report instrument. Sixty-six patients were randomized to receive glutamine and 68 to receive the placebo preparation. There were no significant differences or substantial trends in the mucositis scores between the two study arms as measured by either the physicians or the patients. It was concluded that the dose and schedule of glutamine used in this clinical trial does not alleviate 5-FU-induced mucositis.

Background: Randomized trials of colony-stimulating factors in febrile patients with neutropenia after chemotherapy have not consistently shown clinical benefit. Nevertheless, the use of colony-stimulating factors to treat patients with chemotherapy-induced neutropenia is widespread., Methods: We performed a randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor (G-CSF) in afebrile outpatients with severe chemotherapy-induced neutropenia. We measured the number of days of neutropenia, rate of hospitalization, number of days in the hospital, number of days the patient received parenteral antibiotics, and number of culture-positive infections., Results: We randomly assigned 138 patients to receive G-CSF (n=71) or placebo (n=67). The median time to an absolute neutrophil count of at least 500 per cubic millimeter was significantly shorter for patients who received G-CSF (two days, vs. four days for the patients given placebo). However, there was no effect on the rate of hospitalization, number of days in the hospital, duration of treatment with parenteral antibiotics, or number of culture-positive infections., Conclusions: Routine therapeutic application of G-CSF in afebrile patients with severe neutropenia can reduce the duration of neutropenia, but this does not appear to provide practical clinical benefit.

Because of its unusual mechanism of action, docetaxel was selected for study in advanced soft tissue sarcomas of adults as part of a search for new active antisarcoma agents. Patients at least 18 years old with measurable histologically proven advanced nonosseous sarcomas were enrolled if they had ECOG performance status of < or = 2 and satisfactory leukocyte and platelet counts, and hepatic and renal function. Patients with Kaposi's sarcoma, mesothelioma, meningioma, embryonal rhabdomyosarcoma, and extraosseous Ewing's sarcoma were excluded, as were patients with brain or leptomeningeal metastases. Other specific contraindications to participation included other active cancer, previous or concurrent cancer chemotherapy or immunotherapy, and known allergy to the drug vehicle, polysorbate 80. Women of childbearing potential were required to have a negative pregnancy test. Following premedication with dexamethasone and diphenhydramine hydrochloride, docetaxel 100 mg/m2 as a concentrated solution containing 40 mg/ml in polysorbate 80 was infused over 1 h in 250 ml of either dextrose 5% in water or 0.9% saline. Treatment was repeated at 3-week intervals using standard definitions for objective responses. Up to two separate 25% toxicity directed dose reductions were permitted. Between May and December 1993, nine men and nine women registered (median age, 44 years). They received a total of 51 cycles of docetaxel (median, 2.5 cycles). Toxicity included moderate leukopenia (median first cycle nadir, 1.5 x 10(9)/L) but no significant thrombocytopenia. Alopecia, diarrhea, nausea, vomiting, and anorexia were common side effects. Fever, minor skin rashes, stomatitis, and edema were also observed. One drug-related death occurred in a neutropenic patient. One partial regression was observed (5.9%, 95% C.I. 0.15-28.7%) among the 17 eligible patients in a patient with metastatic uterine leiomyosarcoma.

A phase II combination chemotherapy protocol combining methotrexate, vinblastine, doxorubicin, and cisplatin was designed to evaluate tumor response and survival in patients with advanced/recurrent endometrial carcinoma. Thirty patients with advanced/recurrent endometrial carcinoma were assigned to chemotherapy treatment at 4-week intervals with methotrexate 30 mg/m2 i.v. Days 1, 15, and 22; vinblastine 3 mg/m2 i.v. Days 2, 15, and 22; doxorubicin 30 mg/m2 i.v. Day 2; and cisplatin 70 mg/m2 i.v. Day 2. After a median of four cycles (maximum number two cycles beyond complete regression; minimum six cycles for stable partial regression), we observed objective regression in 20 patients (67%) (95% CI, 50, 84) with complete regression in 8 patients (27%) and partial regression in 12 patients (40%). Median overall survival was 9.9 months (range, 0.3-34.2), and median survival of responders was 11.0 months (range, 2.6-34.2) from initial date of response. Toxicity was substantial with two treatment-related deaths and consisted predominantly of neutropenia (grade 3 or greater in 93% of the patients), alopecia, nausea, emesis, stomatitis, and azotemia. In conclusion, MVAC is a highly active outpatient chemotherapy regimen in patients with advanced/recurrent endometrial carcinoma, achieving a high complete and partial response rate. Toxicity is substantial in this elderly patient population.

A phase II combination chemotherapy protocol combining methotrexate, vinblastine, doxorubicin, and cisplatin was designed to evaluate tumor response and survival in patients with advanced/recurrent cervix and vaginal cancer. Twenty-nine patients with advanced/recurrent cervix cancer and three patients with advanced vaginal cancer who had not previously received cytotoxic chemotherapy were assigned to chemotherapy treatment at 4-week intervals with methotrexate 30 mg/m2 i.v., Day 1, vinblastine 3 mg/m2 i.v., Days 2, 15, and 22, doxorubicin 30 mg/m2 i.v., Day 2, and cisplatin 70 mg/m2 i.v., Day 2. After a median of 4 cycles (maximum number 2 cycles beyond complete regression; 6 cycles with stable regression); we observed objective regressions in all 3 patients with vaginal cancer and 19 patients (66%, 95% CI = 46.82) with cervix cancer including complete regression in 6 patients (21%, 95% CI = 8.40) and partial regression in 13 patients (45%, 95% CI = 26.64). Median overall survival was 11.5 months (range 1.1-54+). Median survival of responders was 12.8 months (range 3.6-54+). Toxicity included neutropenia, alopecia, nausea, emesis, and stomatitis. Although grade 3 and 4 neutropenia was observed in over half of the patients, there were no treatment-related deaths. In conclusion, MVAC is a highly active outpatient chemotherapy regimen in patients with advanced/recurrent cervix cancer, achieving a high complete and partial response rate with moderate hematologic toxicity. These results need to be confirmed by phase III trial in advanced disease patients and MVAC may be a suitable regimen for investigation in neoadjuvant chemotherapy trials in poor prognosis, previously untreated patients.

Background: In an effort to identify new active chemotherapeutic agents against non-small cell lung cancer (NSCLC), the authors conducted a randomized Phase II trial to evaluate the efficacy of amonafide or trimetrexate in patients with Stage IV disease., Methods: This was a multicenter Cooperative Oncology Group trial. All patients had advanced NSCLC and were previously untreated with chemotherapy. Patients were randomized to treatment after enrollment. Amonafide was administered as a 24-hour continuous infusion (1600 mg/m2) every 21 days. Trimetrexate (150 mg/m2) was administered intravenously over 30 minutes every 2 weeks. The primary endpoints of the study were clinical response and toxic effects. All patients were observed for survival., Results: Thirty-five patients received amonafide and were assessable. There were no complete responses and two partial responses (6%). Thirty-seven patients were treated with trimetrexate. There were no complete responses and five (14%) partial responses. Myelosuppression was the primary toxic effect observed with amonafide treatment. Trimetrexate was associated infrequently with clinically significant side effects., Conclusions: Amonafide is inactive against NSCLC, and no additional studies with this agent are planned. Trimetrexate has some activity against NSCLC, but its role in the future therapy of this disease is questionable.

Preliminary information has suggested that megestrol acetate leads to appetite stimulation and nonfluid weight gain in patients with breast cancer, other cancers, and AIDS. Pursuant to this, we developed a randomized, double-blind, placebo-controlled trial of megestrol acetate in patients with cancer-associated anorexia and cachexia. We randomly assigned 133 eligible patients to receive 800 mg of megestrol acetate per day or a placebo. Patients assigned to megestrol acetate more frequently reported improved appetite (P = .003) and food intake (P = .009) when compared with patients receiving the placebo. A weight gain of 15 lb or more over baseline was seen in 11 of 67 (16%) patients receiving megestrol acetate compared with one of 66 (2%) given the placebo (P = .003). Patients receiving megestrol acetate reported significantly less nausea (13% vs. 38%; P = .001) and emesis (8% vs. 25%, P = .009). No clinically or statistically significant toxic reactions were ascribed to megestrol acetate, with the exception of mild edema. This study convincingly demonstrated that megestrol acetate can stimulate appetite and food intake in patients with anorexia and cachexia associated with cancer, leading to significant weight gain in a proportion of such patients.

Between March 1985 and January 1987, 103 women with histologically proven stage III-IV ovarian carcinoma were randomly allocated to groups receiving monthly intravenous regimens of 1 g of cyclophosphamide/m2 plus either 60 mg of cisplatin (CDDP)/m2 or 150 mg of carboplatin (CBDCA)/m2 for 1 year unless disease progressed earlier. The groups were well balanced according to the stratification factors (age, histologic differentiation, extent of residual disease, and performance score), and both treatments were well tolerated and produced similar median first-course leukopenia (2,200 and 2,000 cells/microL) and thrombocytopenia (220,000 and 202,500 cells/microL). The CBDCA regimen was less emetogenic. After an interim analysis in January 1987 revealed superior progression-free survival for the group of 53 patients receiving CDDP (P = .005), the study was closed to further accrual. Those 24 patients still receiving CBDCA were encouraged to cross over to the CDDP-based regimen and 21 of them did. Following treatment crossover, the relative risk of death associated with original allocation to CBDCA receded from 1.79 to 0.97, indicating success of the salvage treatment using the CDDP-based regimen. This aborted study demonstrated the superiority of CDDP over CBDCA when the two platinum compounds were compared at equally myelosuppressive low doses in combination with 1 g of cyclophosphamide/m2. If CDDP is to be supplanted by CBDCA, larger, more myelosuppressive doses of CBDCA will be required. The platinum drug antitumor effect is a critically important therapeutic feature of this combination.

We studied the clinical applicability of a recently developed technic that determines antiplatelet antibody directly on the platelet surface or in serum. The technic is a quantitative complement lysis-inhibition assay. Normal platelets have less than 0.4 pg of surface IgG. All patients with idiopathic thrombocytopenic purpura who were studied had greater than that value. Surface IgG was increased in inverse proportion to the platelet count. Surface levels of greater than 1.1 pg correlated with failure to respond to prednisone therapy. Incubation of normal serums with normal platelets did not increase surface IgG of such platelets, but the incubation with thrombocytopenic serums increased their surface IgG 0.5 to 100 times. The degree of increase did not predict response to treatment. However, quantitation of surface IgG of thrombocytopenic platelets was useful in predicting response to treatment.