S. Malamud

Squamous-cell carcinoma of the anus in HIV-positive patients

PURPOSE: Patients diagnosed as having anal cancer and human immunodeficiency virus (HIV)-positive disease were evaluated for response to treatment and its associated toxicity. METHODS: We studied nine HIV-positive patients with squamous-cell carcinoma of the anus. Among them, three patients had acquired immunodeficiency syndrome (AIDS). The stage of disease at presentation included: one Stage 0, two Stage I, two Stage II, and four Stage III patients. Seven patients received combined modality treatment,i.e.,radiation therapy and chemotherapy, and two patients received radiation therapy alone. The radiation therapy field included the pelvis and a conedown boost. Chemotherapy consisted of two cycles of 5-fluorouracil and mitomycin C. Patients have been followed from 2 to 42 (median, 8) months. RE-SULTS: Seven patients achieved a complete response clinically. All Stage I/II patients and one of four Stage III patients remain alive and have no evidence of disease. Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer Grades 3 and 4 skin toxicity were noted in six patients, and Grades 2 and 3 myelosuppression were noted in eight patients. The response rates achieved are comparable to the experience in non-HIV patients reported in the literature, but toxicity seems to be increased. CONCLUSION: It would seem reasonable to offer combined modality treatment to early stage, HIV-positive patients with good performance status and a history of minor opportunistic infections. The value of combined modality in AIDS patients and those who present with advanced stages of the disease is questionable.

l-Carnitine Supplementation for the Treatment of Fatigue and Depressed Mood in Cancer Patients with Carnitine Deficiency: A Preliminary Analysis

Abstract: Nutritional factors are among the postulated causes of fatigue, a highly prevalent symptom in the cancer population, with serious impact on patients’ quality of life. Deficiency of the micronutrient carnitine may play a role by reducing energy production through fatty acid oxidation. We present preliminary data of an open‐label, dose‐finding study to determine safety and maximally tolerated dose (MTD) of 1 week of l‐carnitine supplementation in cancer patients with fatigue and carnitine deficiency. Patients who met inclusion/exclusion criteria underwent carnitine level determination. Eighty‐three percent of these patients (15/18) had carnitine deficiency. Preliminary data analysis of 13 patients showed that total carnitine increased from 30.0 ± 6.9 to 41.0 ± 12.1 (mean ± SD) after 1 week of supplementation (P= 0.01), and free carnitine increased from 24.3 ± 6.1 to 33.8 ± 9.8 (P= 0.004). Outcome measures were fatigue (BFI score), depression (CES‐D), sleep disruption (ESS), and performance status (Karnofsky). Median (min, max) BFI score at baseline was 73 (46, 82) versus 50 (3, 82) after 1‐week supplementation (P= 0.009). CES‐D score at baseline was 29 (16, 42) and 22 (8, 32) after 1 week (P= 0.028). ESS at baseline was 46.5 (0, 69) and 30.4 (0, 72) after 1 week (P= 0.015). Karnofsky score did not change significantly (P= 0.38). We are currently conducting a randomized, double‐blind, placebo‐controlled study to rigorously assess the role of l‐carnitine for the treatment of fatigue and depression in cancer patients.

L-carnitine supplementation in patients with advanced cancer and carnitine deficiency: a double-blind, placebo-controlled study.

Carnitine deficiency is prevalent in populations with chronic illness, including cancer. In a recent open-label study, L-carnitine supplementation was well tolerated and appeared to improve fatigue and other outcomes in cancer patients. To further evaluate this finding, adult patients with advanced cancer, carnitine deficiency (free carnitine more than 35 micromol/L for males or less than 25 micromol/L for females, or acyl/free carnitine ratio of more than 0.4), moderate to severe fatigue, and a Karnofsky Performance Status (KPS) score of 50 or more, were randomly assigned to receive either L-carnitine (0.5 g/day for two days, followed by 1g/day for two days, and then 2g/day for 10 days) or placebo. This double-blind phase was followed by an open-label phase, during which all patients received L-carnitine supplementation for two weeks. Outcomes included the fatigue subscale of the Functional Assessment of Cancer Therapy-Anemia (FACT-An), the Linear Analog Scale Assessments (LASA), the Mini-Mental State Exam (MMSE), and the KPS. Twenty-nine patients (12 placebo, 17 L-carnitine) were included in the intent-to-treat (ITT) analysis. From baseline to the end of the double-blind phase, serum total and free L-carnitine increased from 32.9+/-3.8 to 56.6+/-20.5 (P=0.004), and from 22.9+/-19.4 to 45.3+/-17.2 (P=0.004), respectively, in the L-carnitine-treated group, and from 28.2+/-10.2 to 36.2+/-8.7 (P=ns), and from 22.6+/-7.9 to 28.7+/-8.6 (P=ns) in the placebo group, respectively. The planned ITT analysis revealed no significant improvement in any of the studys endpoints, and these negative findings were not different when data from two patients who did not adhere to the protocol were eliminated. However, an exploratory covariate analysis that excluded these two protocol violators and included outcome data from both the double-blind and open-label phases demonstrated significantly improved fatigue on the FACT-An fatigue subscale (P<0.03), and significantly improved FACT-An functional well-being subscale (P<0.03), and KPS (P<0.003), in the group that started with L-carnitine during the double-blind phase. These data do not support the conclusion that L-carnitine in the doses tested reverses cancer-related fatigue in carnitine-deficient patients. However, L-carnitine supplementation does increase L-carnitine serum levels, and the positive findings in an exploratory analysis justify a larger study to determine if this strategy could be of benefit for a subpopulation of cancer patients.

Adoptive chemoimmunotherapy for the treatment of relapsed and refractory solid tumors using ex vivo activated memory T cells (autolymphocyte therapy) and cyclophosphamide

Autolymphocytes (ALT cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor specific CD45RO+ (memory) T cells. These ALT cells combined with cimetidine as autolymphocyte therapy (ALT) have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). To determine activity of ALT in human TBH with therapy-resistant solid tumors other than RCC and whether it was feasible to combine ALT with chemotherapy, we studied 21 patients with relapsed or primary refractory solid tumors following a study protocol of adoptive chemoimmunotherapy (ACIT) using ALT and cyclophosphamide. Twenty patients were evaluable. Five responses were seen, including two complete responses (CRs) and three partial responses (PRs). ACIT activity was noted in relapsed TBH who had responded to their previous chemotherapy and/or radiation therapy. The toxic effects of this ACIT study were minimal with no treatment-related morbidity or mortality. It appears that in some relapsed but not primary refractory solid tumors, ACIT using ALT (CD45RO+ T cells and cimetidine) together with cyclophosphamide has definite antitumor activity associated with little or no toxic effects. Further studies of ACIT in solid tumors other than RCC are justified.

A Pilot Study of Chemotherapy Alternating with Twice-a-Day Accelerated Radiation Therapy as an Alternative to Cystectomy in Muscle Infiltrating (Stages T2 and T3) Cancer of the Bladder: Preliminary Results

Laboratory studies have suggested that rapidly alternating chemotherapy and accelerated radiation therapy might act synergistically. We evaluated the toxicity and effectiveness of this approach in muscle infiltrating transitional cell carcinoma of the bladder in patients who were poor risks for or who refused cystectomy. We treated 18 men and 3 women with stage T2 or T3 transitional cell carcinoma of the bladder by transurethral resection, followed by 3 cycles of chemotherapy (during weeks 1, 4 and 7) rapidly alternating with 3 cycles of twice-a-day radiation therapy (during weeks 2, 5 and 8). Chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin. The total dose of radiation therapy was 5,400 to 6,000 cGy, during 6 1/2 weeks and the total duration of chemotherapy and radiation therapy was 7 1/2 weeks. One patient died of hematological toxicity during treatment. With a median followup of 2 years (range 0.5 to 5.5 years) the observed survival rate was 72% at 2 years and 60% at 3 years. To date, only 1 patient (5%) had recurrence of invasive cancer in the pelvis. Only 3 others (15%) had carcinoma in situ but to date none has required cystectomy. Bladder function was normal in 15 of 18 evaluable patients (83.5%). This pilot study suggests that chemotherapy alternating with radiation therapy produced an encouraging survival rate without cystectomy and deserves further study. These patients require continued surveillance for carcinoma in situ.

Phase I dose-finding study of biweekly irinotecan in combination with fixed doses of 5-fluorouracil/leucovorin, gemcitabine and cisplatin (G-FLIP) in patients with advanced pancreatic cancer or other solid tumors.

This phase I trial was initiated based on encouraging clinical data with 5-fluorouracil (5-FU)/leucovorin (LV), gemcitabine and cisplatin (G-FLIP) in the therapy of solid tumors. In this trial, G-FLIP has been modified to facilitate outpatient administration and to optimize sequence-dependent synergistic activity. Treatment consisted of biweekly (once every 14 days) cycles of sequential gemcitabine 500 mg/m2, irinotecan per dose escalation schedule, bolus 5-FU 400 mg/m2 and LV 300 mg on day 1 followed by a 24-h 5-FU infusion 1500 mg/m2, followed by cisplatin 35 mg/m2 on day 2. The irinotecan starting dose was 80 mg/m2 and escalated by 20 mg/m2 in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Twenty-three patients were enrolled (13 men/10 women) with the following cancers: 11 pancreatic, five gallbladder, three squamous cell carcinoma of the head and neck, one hepatocellular carcinoma, one melanoma, one gastric, and one breast cancer. Median patient age was 63 years (range 44–78) and median Karnofsky performance status (KPS) was 80. Patients received a median of 8 cycles (range 1–16) over five irinotecan dose levels (80, 100, 120, 140 and 160 mg/m2). Dose-limiting toxicity consisting of grade 3 nausea/vomiting despite aggressive anti-emetic therapy occurred in one patient at dose level 1 and three patients at dose level 3. Grade 3–4 hematological toxicities per patient consisted of thrombocytopenia (3%), anemia (6%), thrombosis (23%), neutropenia (16%) and neutropenic fever (10%). Of 18 patients evaluable for response, one complete response (pancreatic) and eight partial responses (three gallbladder, two pancreatic, two head and neck, and one breast) were attained. Seven patients had disease stabilization (five pancreatic, one hepatocellular and one gastric) for a median of 16 weeks (range 10–22). Median time to disease progression among all 23 patients enrolled to the phase I portion of the trial was 20.5 weeks (range 4–37). We conclude that G-FLIP is a novel outpatient chemotherapy regimen with acceptable toxicity at the maximum tolerated irinotecan dose of 120 mg/m2. The phase II trial of G-FLIP using an irinotecan dose of 120 mg/m2 for patients with metastatic pancreatic cancer is ongoing.

Chemoradiation in advanced nonsmall cell lung cancer

PURPOSE Resectability, local control, and survival were evaluated in advanced stage nonsmall cell lung cancer treated with simultaneous chemoradiation therapy delivered in an accelerated, interrupted twice-a-day schedule. METHODS AND MATERIALS Forty-seven consecutive patients with Stage IIIA or IIIB nonsmall cell lung cancer, consenting to participation in the study, received cisplatin, 30 mg/m2 for 3 days, etoposid, 80 mg/m2 for 3 days, and 5-fluorouracil, 900 mg/m2 for 4 days. Radiation therapy consisted of 2 Gy given twice a day for 5 days. Two weeks rest was planned between cycles. Patients were evaluated for resectability after the second cycle. Any patient with unresectable tumor received a third cycle of treatment. RESULTS Forty-seven patients were evaluable for acute toxicity: eighteen (38%) required an extended rest period for esophagitis or low blood count; 3 (6%) had sepsis, of whom 1 (2%) expired. Three patients (6%) had multiple blood transfusions for low hemoglobin. Median follow-up is 23.6 months, with a range of 10-49 months. Nine patients (19%) failed locally; 15 (32%) had local and distant failure; 7 (15%) failed only at distant sites. Twelve patients (25.5%) are alive with no evidence of disease; 4 patients were lost to follow-up with disease. The 2-year actuarial survival is 49%, and the 4-year is 28.2%. CONCLUSION Simultaneous chemoradiation is well tolerated with acceptable toxicity. The overall 2- and 4-year actuarial survival is somewhat better than that reported in the literature. Resectability in Stage IIIB patients was not increased with this regimen nor was any surgical specimen free of cancer. The 47% distant failure rate is not different from those reported by others.

Patterns of failure in carcinoma of the upper esophagus after alternating chemoradiotherapy.

Alternating chemoradiotherapy has recently been reported to produce encouraging results in patients with advanced head and neck cancer. We have treated 17 patients with squamous cell carcinoma of the upper esophagus by alternating chemoradiotherapy and by following the patients for 2 to 5 years, or until their death. Chemotherapy (cisplatin and 5-fluorouracil) was delivered during weeks 1, 4, and 7, and radiotherapy (180 to 200 cGy twice each day to 2,000 cGy) during weeks 2, 5, and 8 (total 6,000 cGy). Three patients (18%) died of toxicity (nadir sepsis). All 14 patients who survived the treatment achieved a complete response as shown by endoscopy and biopsy specimens, with restoration of swallowing, and none experienced a local relapse. Three patients died of distant metastases (actuarial incidence 32% at 3 years). The 5-year survival rate was only 16%, however, because 8 other patients with no evidence of the cancer died of a variety of other causes: radiation pneumonitis (1), chronic neutropenia (1), esophageal actinomycosis (1), pneumonia (2), stroke (1), myocardial infarction (1), and small-cell lung cancer (1). Conceivably, some further improvement in the results might occur from cytokines, stem cells, and brachytherapy (by decreasing deaths due to toxicity), but with so many causes of comorbidity it seems unlikely, for the foreseeable future, that the 5-year survival rate could be much improved by better treatment of esophageal cancer.

Phase II Study of Gemcitabine and Bevacizumab As First-Line Treatment in Taxane-Pretreated, HER2-Negative, Locally Recurrent or Metastatic Breast Cancer

BACKGROUND In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine. PATIENTS Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval. METHODS This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%). CONCLUSION Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.

A cluster of vitreoretinal lymphoma in New York with possible link to the Chernobyl nuclear disaster

Vitreoretinal lymphoma (VRL) is an ultra-rare disease and an unusual presentation of primary central nervous system lymphoma (PCNSL) [1]. A quarter of PCNSL patients develop VRL and upto 85% of VRL...