Clay M. Anderson

Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma

PURPOSE Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma. PATIENTS AND METHODS We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m(2) plus paclitaxel 80 mg/m(2) (E + P) or to paclitaxel 80 mg/m(2) alone at a 2:1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc). RESULTS At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated. CONCLUSION E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.

Serial Monitoring of Circulating Tumor Cells Predicts Outcome of Induction Biochemotherapy plus Maintenance Biotherapy for Metastatic Melanoma

Purpose: Molecular biomarkers in blood are promising for assessment of tumor progression and treatment response. We hypothesized that serial monitoring of circulating tumor cells (CTC) with the use of multimarker quantitative real-time reverse transcriptase-PCR assays could be a surrogate predictor of outcome for melanoma patients enrolled in a multicenter phase II clinical trial of biochemotherapy (BCT) combined with maintenance biotherapy (mBT). Experimental Design: Blood specimens were collected from 87 patients before and during induction BCT and mBT for stage IV melanoma. Expression of five melanoma-associated CTC biomarkers (MART-1, GalNAc-T, PAX-3, MAGE-A3, and Mitf) was assessed by quantitative real-time reverse transcriptase-PCR, and correlated with treatment response and disease outcome. Results: The number of positive CTC biomarkers decreased overall during induction BCT (P < 0.0001). CTC biomarker detection after two cycles of BCT was correlated with treatment response (P = 0.005) and overall survival (P = 0.001): an increase in the number of CTC biomarkers was associated with poor response (P = 0.006) and overall survival (P < 0.0001). Multivariate analyses with the use of a Cox proportional hazards model identified the change in CTC biomarkers after two cycles of BCT as an independent prognostic factor for disease progression (risk ratio, 12.6; 95% confidence interval, 4.78-33.4; P < 0.0001) and overall survival (risk ratio, 6.11; 95% confidence interval, 2.37-15.7; P = 0.0005). Conclusion: Serial monitoring of CTC during induction BCT may be useful for predicting therapeutic efficacy and disease outcome in patients receiving BCT and mBT for stage IV melanoma. Clin Cancer Res; 16(8); 2402–8. ©2010 AACR.

Phase II Multicenter Trial of Maintenance Biotherapy After Induction Concurrent Biochemotherapy for Patients With Metastatic Melanoma

PURPOSE Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival. PATIENTS AND METHODS One hundred thirty-three chemotherapy-naïve patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers. The biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo interleukin-2 (IL-2), and interferon alfa-2b with granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine support. Patients not experiencing disease progression were eligible for maintenance biotherapy with low-dose IL-2 and GM-CSF followed by intermittent pulses of decrescendo IL-2 over 12 months. Patients were observed for response, progression-free survival, toxicity, and overall survival. RESULTS The response rate to induction biochemotherapy was 44% (95% CI, 35% to 52%; complete response, 8%; partial response, 36%; stable disease, 29%). The median number of biochemotherapy cycles was four, and the median number of maintenance biotherapy cycles was five. The median progression-free survival was 9 months, and the median survival was 13.5 months. The 12-month and 24-month survival rates were 57% and 23%, respectively. Twenty percent of patients remain alive (12 without disease), with median follow-up of 30 months (95% CI, 25+ to 45+ months). Thirty-nine percent of patients developed CNS metastases. The median times to CNS progression and death were 8 months and 5 months, respectively. CONCLUSION Maintenance biotherapy after induction biochemotherapy seems to prolong progression-free survival and improve overall survival compared with recent multicenter trials of biochemotherapy or chemotherapy. The regimen should be studied in a randomized clinical trial in patients with advanced metastatic melanoma. CNS progression remains a formidable challenge.

Phase II Multicenter Study of Neoadjuvant Biochemotherapy for Patients With Stage III Malignant Melanoma

PURPOSE To determine the relapse-free survival, overall survival, and response rate of patients with stage III melanoma treated with neoadjuvant biochemotherapy in a multicenter setting. PATIENTS AND METHODS Patients with pathologically proven stage III melanoma, either via clinical detection or sentinel lymph node positivity, were eligible for enrollment. Patients received two cycles of preoperative biochemotherapy followed by complete regional lymphadenectomy and two postoperative courses of biochemotherapy. The biochemotherapy regimen consisted of the following: cisplatin 20 mg/m2 on days 1 to 4, dacarbazine 800 mg/m2 on day 1 only, vinblastine 1.6 mg/m2 on days 1 to 4, interleukin-2 total dose of 36 MU/m2 during 4 days, and interferon alfa 5 MU/m2 on days 1 to 5. Growth factor support was administered with each cycle. RESULTS Ninety-two patients were eligible for the study. At a median follow-up of 40.4 months, relapse-free survival and overall survival are 64% and 78%, respectively. There was a lower relapse rate and improved survival for patients with a positive sentinel lymph node compared with patients with clinically detected lymph nodes, although this difference did not reach statistical significance. Of the 50 patients with measurable disease, the overall response rate was 26%. Toxicity of the biochemotherapy was high but generally manageable. CONCLUSION The current study has expanded the preliminary evidence on neoadjuvant biochemotherapy for stage III melanoma.

A phase II study of neoadjuvant biochemotherapy for stage III melanoma

Phase II studies of biochemotherapy (combining interleukin‐2, interferon‐α, and multiagent chemotherapy) have reported high response rates and a significant number of durable complete responses in patients with metastatic melanoma.

A randomized phase III trial of biochemotherapy versus interferon-α- 2b for adjuvant therapy in patients at high risk for melanoma recurrence

The objective of this study was to compare the clinical benefit of biochemotherapy and interferon-&agr;-2b (IFN) as adjuvant therapy. Biochemotherapy has higher response rates than other regimens in patients with metastatic melanoma. We conducted a randomized phase III study comparing the clinical benefit of biochemotherapy and IFN as adjuvant therapy. Patients who had undergone lymphadenectomy for melanoma metastatic to regional lymph nodes were randomly assigned to either biochemotherapy or IFN, and IFN patients were further randomized to either high-dose IFN (HDI) or intermediate-dose IFN (IDI). The primary end point was relapse-free survival (RFS); the secondary end point was overall survival (OS). The planned enrollment was 200 patients, the number required to have 80% power to detect, at a significance level of 5%, an improvement in median RFS from 18 to 36 months and an improvement in median OS from 40 to 80 months between the IFN and biochemotherapy groups. A futility analysis was performed because of slow accrual. One hundred and thirty-eight patients were enrolled – 71 in the biochemotherapy group, 34 in the HDI subgroup, and 33 in the IDI subgroup. No significant differences in median RFS or OS between the HDI and IDI subgroups were observed. With a median follow-up of 49.3 months, neither the biochemotherapy nor IFN group had reached median RFS or OS, and there were no significant differences in estimated median RFS or OS (P=0.86 and 0.45, respectively) between the two groups. Biochemotherapy is not more effective than IFN as adjuvant therapy for melanoma. These findings support early termination of this trial.

Close monitoring and lifetime follow-up is optimal for patients with a history of melanoma

Malignant melanoma, a potentially lethal form of skin cancer, is becoming more common each year in the United States and worldwide. The cure rate, however, is also increasing due to better education, earlier detection, and more effective treatment. Thus, there are more melanoma survivors who are at risk for recurrence of melanoma and also a second primary. Because there are few prospective screening and surveillance results in the medical literature, recommendations for follow-up of melanoma survivors have been based on the natural history of the disease, physical examinations, laboratory tests, and radiologic evaluations.

A Phase II Study of Biochemotherapy for Advanced Melanoma Incorporating Temozolomide, Decrescendo Interleukin-2 and GM-CSF

Metastatic malignant melanoma remains a very difficult disease to treat. Previous phase II studies using biochemotherapy (combination of platinum-containing chemotherapy with IL-2 and IFNα) have shown response rates of about 50%. However, a site of frequent relapse is in the central nervous system (CNS). Temozolomide is an oral alkylating agent that has equivalent activity to dacarbazine, but it has the advantage of CNS penetration. We report the results of a phase II study using a novel biochemotherapy regimen containing temozolomide, cisplatin, decrescendo IL-2, IFNα, and GM-CSF in the treatment of stage IV melanoma. Seventy-one patients with histologically confirmed metastatic melanoma were enrolled between June 1998 and October 1999. Prior chemotherapy or IL-2 was not permitted. The median age was 54 years (range 22–72). Twenty-one patients (30%) had a history of treated brain metastases. Patients received temozolomide 150 mg/m2 orally days 1–5, cisplatin 30 mg/m2 IV days 1–3, IFNα 5 MU/m2 SQ on days 1–5, and IL-2 was administered in a decrescendo fashion according to the following schedule: day 1: 18 MU/m2 continuous IV infusion over 6 hours; day 2: 18 MU/m2 continuous IV infusion over 12 hours; day 3: 9 MU/m2 subcutaneously q12 hours; day 4: 4.5 MU/m2 subcutaneously × 1. Patients were also given GM-CSF 250 µg subcutaneously days 6–25. The cycles were repeated every 4 weeks. Partial responses were seen in 10 of the 71 patients (14%) with a median duration of response of 9.4 months. There were no complete responses. The median survival for all patients was 8.6 months. Further studies of this novel biochemotherapy regimen are not indicated. Other schedules that incorporate temozolomide and/or GM-CSF and further studies to define the optimal method of delivering IL-2 should be pursued.

Nutritional, functional, and emotional characteristics related to fatigue in patients during and after biochemotherapy

PURPOSE/OBJECTIVES To test Winninghams psychobiologic entropy hypothesis in patients receiving biochemotherapy for melanoma. DESIGN Descriptive, correlational, cross-sectional study. SETTING Midwest cancer center. SAMPLE 25 male and female patients who were receiving biochemotherapy or who had completed treatment 6-12 months prior. METHODS Data were collected using a series of questionnaires and diet recall. MAIN RESEARCH VARIABLES Fatigue, anxiety, depression, distressing symptoms, nutritional intake, and weight. FINDINGS Moderate fatigue was significantly related to physiologic and psychological symptoms but not to nutrient intake. The sample was overweight, and a significant number of participants were obese. High caloric intakes were evident. Depression was a significant problem. CONCLUSIONS Fatigue was not as severe as expected, but problems with responses to the fatigue scale may explain this. Nutritional status and nutrient intake were not correlated to fatigue in this sample. Activity levels were related to fatigue, and treatment reduced activity. On average, activity returned to pretreatment levels 6-12 months after treatment. Winninghams hypothesis held and will be useful for understanding fatigue in this population. IMPLICATIONS FOR NURSING Depression needs to be assessed and treated as a side effect of biotherapy. Assessing the impact of nutrition when patients are overweight or obese is difficult. A scale specifically designed to test Winninghams hypothesis is needed.

Nutritional Palliative Care Issues

Food and nutrition have social, spiritual, and cultural overlaying meanings beyond their importance to the biological integrity of human beings. The balance of benefit and burden with natural and artificial nutrition and hydration is complex and dynamic. Total parenteral nutrition (TPN) may be helpful if the GI tract is not working and the illness and/or the complication is reversible and there is a reasonable likelihood of significant recovery. Oral, gastrointestinal (GI), or intravenous (IV) intake can be a net harm to the actively dying person who is not always capable of taking in or utilizing nutrients and water. Medical nutrition and hydration should cease before net harm occurs, but defining the moment of net harm remains a challenge to healthcare providers. The goals of nutrition should be considered in a patient with poor functional status and prognosis. Artificial nutrition and hydration should only be used as a bridge to attain a functional or quality of life goal as defined by the patient with a life-limited diagnosis. Artificial nutrition and hydration are optional at the end of life and the burdens and benefits must be considered. The perspectives of various stakeholders regarding the role of food and water, nutrition and hydration at the end of life are important to consider. Issues surrounding artificial nutrition elicit strong emotional responses, making effective communication with the patient/family unit about food and nutrition and fluid essential.