Albert S. Alberts

Dose response relationship and multiple dose efficacy and toxicity of samarium-153-EDTMP in metastatic cancer to bone

INTRODUCTION The optimal dose of samarium-153-EDTMP (153Sm-EDTMP) for effective palliation of painful metastases to bone is under investigation. It is not known whether increased doses of 153Sm EDTMP will lead to better and longer pain and tumour control and survival. Multiple dose efficacy and toxicity is of importance as most Patients will require prolonged support for pain. METHODS Twenty-eight (28) patients were treated with 0.75 mCi/kg, 35 patients with 1.5 mCi/kg and 19 patients with 3 mCi/kg in three sequential Phase I-II trials. Multiple doses were given to patients on the 0.75 mCi/kg and 1.5 mCi/kg dose levels. RESULTS At all dose levels adequate pain control was achieved in 78-95% of patients. The duration of pain control was 40-56 days with the best results in the 1.5 mCi/kg group (56 days). There is no evidence that increasing dose leads to better and longer pain control, tumour response and survival, but toxicity is increased. Multiple doses can be given with acceptable toxicity and pain control, however, only 38% of patients will qualify for multiple treatments. CONCLUSION 153Sm-EDTMP provides adequate and safe palliation but multiple doses can only be given in 38% of patients. There is not a clear dose-response relationship. The length of pain control is satisfactory but not ideal and hospitalisation for 4 days every 6-8 weeks is a disadvantage. Further research is required to combine 153Sm-EDTMP with cytostatics and to administer it on an out patient basis.

Evaluation of samarium-153 and holmium-166-EDTMP in the normal baboon model

Bone-seeking radiopharmaceuticals such as ethylenediaminetetramethylene phosphonate (EDTMP) complexes of samarium-153 and holmium-166 are receiving considerable attention for therapeutic treatment of bone metastases. In this study, using the baboon experimental model, multicompartmental analysis revealed that with regard to pharmacokinetics, biodistribution, and skeletal localisation, 166Ho-EDTMP was significantly inferior to 153Sm-EDTMP and 99mTc-MDP. A more suitable 166Ho-bone-seeking agent should thus be sought for closer similarity to 153Sm-EDTMP to exploit fully the therapeutic potential of its shorter half-life and more energetic beta radiation.

Phase 2 study of single-agent IV vinflunine as third-line treatment of metastatic breast cancer after failure of anthracycline-/taxane-based chemotherapy.

Objective:A multicenter, open-label, phase 2 study evaluated the efficacy and safety of intravenous vinflunine as third-line treatment in patients with progressing metastatic breast cancer (MBC) after failure of anthracycline- and taxane-based chemotherapy. Patients and Methods:Fifty-six patients with MBC, relapsing after receiving 2 previous treatments for advanced disease, including both anthracyclines and taxanes, received 320 mg/m2 of vinflunine once every 3 weeks (median number of 2.5 cycles, range: 1–13). Results:According to an independent radiologist, the response rate was 12.5% (95% CI: 5.2–24.1) and 14% (95% CI: 5.3–27.9) (6 partial responses) in the treated and evaluable populations, respectively. Disease control was achieved in 42.9% and 51.2% of the patients, respectively. Median progression-free survival was 2.6 months (95% CI: 1.6–4.0 months) with a median overall survival of 11.4 months (95% CI: 7.4–14.2 months). Duration of response was 6.8 months (95% CI: 5.6 months, upper limit not reached). Leukopenia was the most frequent hematologic toxicity, with grade 3/4 severity in 49.1% of the patients. Grade 3 neutropenia in 30.9%, grade 4 in 40.0% of patients, febrile neutropenia (5.4%), and 1 case of neutropenia infection (1.8%) were reported. Other grade 3 toxicities included anemia (5.5%), fatigue (14.3%), and constipation (7.1%), which were noncumulative. The adverse events associated with vinflunine were predictable and manageable. Conclusions:Vinflunine is an active and well-tolerated agent as third-line treatment of patients with MBC after failure of anthracycline- and taxane-based therapy. These results warrant further investigation of vinflunine monotherapy or in combination for the treatment of MBC.

The value of radiotherapy or chemotherapy after intubation for advanced esophageal carcinoma — A prospective randomized trial

After intubation for advanced, inoperable squamous carcinoma of the oesophagus, a prospectively controlled randomized trial was done to investigate the effect of radiotherapy (41 patients) or mono-chemotherapy (40 patients) or no further treatment (46 patients). Treatment had no significant effect on either palliation or survival (p < or = 0.7) and did not alter the natural history of the disease.

Trimetrexate in advanced carcinoma of the esophagus

SummaryTwenty-four patients with advanced epidermoid carcinoma of the esophagus were treated with trimetrexate (TMTX), a lipid soluble non-classical antifol. Patients were given TMTX 8 mg/m2 intravenously day 1–5 every 28 days. In nine of these patients the dose was escalated to 12 mg/m2 day 1–5 every 28 days. Three patients had a partial response (95% confidence limit 3–32%) with a median response duration of 14 weeks. No hematologic toxicity was documented. Two patients developed moderate stomatitis and only 3 patients experienced any nausea or vomiting. The median survival of all patients is 12 weeks. It is concluded that a higher dose of TMTX should be studied in patients with esophageal cancer in order to assess the true therapeutic value of the agent at a dose closer to the median tolerated dose. A phase II ECOG study using TMTX 12 mg/m2 intravenously day 1–5 every 21 days is currently being conducted.

Ifosfamide in advanced carcinoma of the esophagus: A phase II trial with severe toxicity

Seventeen patients with advanced epidermoid carcinoma of the esophagus were treated with ifosfamide (IFOS) 1.5 mg/m2/day intravenously on days 1–5 every 28 days. Mesna was given concurrently at 20% of the IFOS dose prior to and 4 and 8 h after IFOS for uroprotection. Toxicity in this trial was severe since life-threatening leukopenia occurred in one patient, Grade 3 nausea and vomiting (necessitating termination of treatment) in two patients, and Grade 3 neurotoxicity (cerebellar dysfunction) in two patients. Two patients developed severe infections (Grade 3). Only four patients experienced no toxicity. One patient had a partial response with a response duration of 8 weeks. The median survival of all patients is 10 weeks. It is concluded that IFOS as given in this trial has limited activity in esophagus carcinoma with severe toxicity.

Normalization of skin appearance in a patient with scleromyxoedema after intensive chemotherapy for Hodgkin's disease

A patient with scleromyxoedema was treated for 6 years with cytostatic drugs. During this time the skin lesions followed a fluctuating but progressive course. After 6 years she developed Hodgkins lymphoma of the mixed cellularity type. Intensive cytostatic treatment given for Hodgkins disease resulted in virtually complete disappearance of the scleromyxoedema lesions. The development of Hodgkins disease is considered fortuitous and not due to the previous cytostatic drugs.

A phase II study of idarubicin and prednisone in multiple myeloma.

Twenty-one patients with multiple myeloma were treated with idarubicin 45 mg/m2 orally day 1 and prednisone 60 mg/m2 day 1-4 every three weeks. Moderate to severe gastrointestinal and hematopoietic toxicity were observed. Twelve of the twenty-one patients had relapsed on prior treatment. Of these, 2 patients responded. Two patients had primary resistant disease, neither responded. Seven patients had no prior treatment, three responded. ldarubicin and prednisone have modest activity in refractory myeloma, with short duration of response and severe toxicity.

A phase II study of 5-fluorouracil and leucovorin in advanced carcinoma of the esophagus.

Thirty-five patients with advanced epidermoid carcinoma of the esophagus were treated with 5-fluorouracil (5-FU) 425 mg/m2 and leucovorin 20 mg/m2, day 1–5 every 28 days. Six patients had a partial response (95% confidence limit, 7–35%) with a median response duration of 32 weeks. The median survival time of the patients on study was 14 weeks. The toxicity was acceptable, with only two patients experiencing severe hematologic toxicity and one patient experiencing severe nausea and vomiting. The addition of leucovorin at this dose level in this population of patients with advanced disease does not appear to enhance the activity of 5-FU for patients with squamous cell cancer of the esophagus. Since only a small percentage of patients experienced significant toxicity, a higher response rate could be achieved in patients treated with the maximally tolerated dose.