A Phase I dose escalation trial of continuous infusion paclitaxel to augment high dose cyclophosphamide and thiotepa plus stem cell rescue for the treatment of patients with advanced breast carcinoma

BACKGROUND: Paclitaxel, an effective chemotherapeutic agent in the management of breast carcinoma, may have activity in women whose disease has recurred after high dose chemotherapy. With this is mind the authors explored the addition of a 120-hour continuous infusion of paclitaxel to a previously reported regimen comprised of high dose cyclophosphamide and thiotepa. METHODS: Thirty-one women with advanced breast carcinoma (30 patients with Stage IV disease and 1 patient with Stage IIIB disease) underwent harvest and cryopreservation of bone marrow and/or peripheral blood progenitor cells. High dose cyclophosphamide (2.5 g/m2) and thiotepa (225 mg/m2) were administered intravenously on Days -7, -5, and -3. Paclitaxel was administered as a 120-hour continuous infusion starting on Day -7. RESULTS: Three patients were treated at the initial cohort dose of 50 mg/m2 (over 120 hours), 6 patients at 100 mg/m2, 6 patients at 125 mg/m2, 6 patients at 150 mg/m2, 6 patients at 180 mg/m2, and 4 patients at 210 mg/m2. All patients completed the treatment protocol as planned with no associated transplant-related deaths. Mucositis as evidenced by either stomatitis or noninfectious diarrhea was experienced by all patients and was determined to be the dose-limiting toxicity at the 210 mg/m2 dose level. One patient with dose-limiting mucositis required intubation for airway protection and also experienced Grade 3 (according to the Cancer and Leukemia Group B common toxicity grading scale) pulmonary and neurologic toxicity. Only one Grade 3 toxicity was encountered below the maximum tolerated dose in a patient who developed diffuse alveolar hemorrhage at a dose of 125 mg/m2. No allergic reactions or clinical evidence of peripheral neuropathies were encountered. Cardiac, hepatic, and renal toxicities were minimal. Response rates in this previously treated patient population were difficult to assess in light of the high incidence of bone metastases; an overall response rate of 24% was obtained. CONCLUSIONS: Paclitaxel at a dose of 180 mg/m2 as a 120-hour continuous infusion may be added safely to high dose cyclophosphamide and thiotepa with autologous stem cell rescue. Further studies are ongoing to evaluate the efficacy and further define the toxicity of this recommended Phase II dose.     

The evidence for increasing cytotoxic dose intensity in the treatment of advanced ovarian cancer

Clinically, lipomas of the hypopharynx may be confused with other benign or even malignant lesions. Barium flow radiography allows depiction of lesions cranial to the epiglottis, but often fails to be accurate for subepiglottic lesions. CT however has allowed a certain diagnosis to be made in many cases in the past. MRI is still more accurate, and allows not only a more specific diagnosis of the lesion, but also a better depiction of the origin of the pedunculated lesion and its extension in the parapharyngeal space. This paper adds three cases to the 52 cases in the literature already described and presents the typical features of hypopharyngeal lipoma by MRI for the first time.     

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

A retrospective analysis was done of the results of the Pemberton osteotomy for the treatment of developmental dysplasia of the hip in 16 hips of 14 children older than 7 years. The average age of the patients at the time of surgery was 11+6 years and the average follow-up was 4+10 years. Eleven hips required one or more surgical procedures concomitant with the Pemberton osteotomy to achieve a concentric and congruous reduction of the hip joint. None of the hips developed avascular necrosis of the acetabular fragment. The center-edge angle improved from a preoperative average of 1 degree to an average of 30 degrees at the most recent follow-up. Correction of acetabular dysplasia was noted in 14 of the 16 hips, as demonstrated by the improvement in the acetabular index, the center-edge angle, and the Severin class. We believe that the Pemberton osteotomy can be a safe and effective procedure for the treatment of developmental dysplasia of the hip in the older child.     

Doxorubicin hydrochloride, cyclophosphamide, and 5-fluorouracil combination in advanced prostate and transitional cell carcinoma

Hubbard cockerels, 1 day of age (n = 91), were divided into 3 handling groups: (1) chicks from the 5-Day group were removed from the brooder and isolated at 22 degrees C for 3 min on each of the first 5 days; (2) chicks from the 15-Day group received this treatment for 15 days; and (3) Control chicks were not handled. Within each group half were fed broiler starter for 5 weeks, and half were fed layer starter which produces slower growth. On Days 28, 35, 42, and 49 the average weight of 5-Day birds was significantly higher than that of Controls; 15-Day birds weighed slightly less than birds in the 5-Day group. The weight advantage of the 5-Day birds occurred with both starter rations, at all weighing periods, and did not appear to reflect increased food consumption. Similarities between these findings and results obtained with rodents were noted.     

Carboplatin in combination with epirubicin and cyclophosphamide in patients with advanced ovarian cancer. A phase II study

Seventy-one patients with epithelial ovarian cancer stage III (n = 56) or IV (n = 15) were treated with carboplatin 300 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 400 mg/m2 every fourth week. Patients clinically free of tumour after six courses (n = 58) underwent a second-look laparotomy. Seventeen patients were microscopically tumour-free (24% of all) and an additional 10 (14%) had only microscopic cancer. Median time to progression was 19 months. The median survival was 33 months and the estimated 5-year survival 27%. The toxicity was mainly haematological, with leukopenia WHO grade 3-4 seen in 88% and thrombocytopenia grade 3-4 in 42% of the patients. The gastrointestinal toxicity was mild and no renal toxicity was seen. This chemotherapy regimen was effective with acceptable toxicity and could be given on an out-patient basis. The possibility of increasing the efficacy and decreasing the toxicity was discussed.     

Multimodality treatment of 128 patients with locally advanced breast carcinoma in the era of mammography screening using standard polychemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide: prognostic and therapeutic implications

BACKGROUND: Locally advanced breast carcinoma is associated with a poor prognosis. With single treatment modalities, i.e., surgery and/or radiation therapy, results have been consistently dismal. However, several earlier reports have indicated improvement in survival with a combined modality approach, i.e., the utilization of systemic therapy. METHODS: Between 1991 and 1994, 128 patients with locally advanced noninflammatory or inflammatory breast carcinoma (LABC) were treated with a combined modality strategy consisting of 4-6 courses of preoperative 5-fluorouracil (600 mg/m2), epirubicin (60 mg/m2), and cyclophosphamide (600 mg/m2) (FEC) every 3 weeks, followed by modified radical mastectomy or sector resection with axillary dissection in combination with postoperative radiotherapy and concomitant cyclophosphamide (850 mg/m2). Postoperatively, 3-5 adjuvant courses of FEC therapy were given. Nine percent of the patients received preoperative radiotherapy because the FEC therapy was not sufficiently effective. One-third of the patients were given tamoxifen (20 or 40 mg daily) at the end of the multimodal therapy. RESULTS: Clinical responses were observed in 60% of the patients; 5% had complete responses (CR) and 55% had partial responses (PR). Stable disease (SD) was observed in 40%. No patient had progressive disease (PD) preoperatively. With a median follow-up of 37 months, the median disease free survival (DFS) and median overall survival (OS) were 29 and 54 months, respectively. The actuarial 5-year DFS and OS were 36% and 49%, respectively. The locoregional recurrence rate was 20%, and 53% of the patients experienced systemic relapse. Univariate analysis revealed a significant prognostic difference according to clinical stage of LABC in favor of less advanced stages. Clinical and biologic parameters linked to a significantly worse prognosis were the presence of inflammatory breast carcinoma and peau d'orange. There was a significant trend of worse prognosis for patients receiving below 60% and 75% of the intended dose intensity with reference to DFS and OS, respectively. CONCLUSIONS: Standard dose preoperative and postoperative FEC therapy combined with surgery and radiotherapy in the era of mammography screening seem to yield results comparable to those achieved with other conventional strategies in the treatment of unscreened populations.     

Second-line treatment with ifosfamide and carboplatin in patients with ovarian carcinoma relapsing after treatment with carboplatin

20 patients with ovarian carcinoma whose disease had relapsed (1-42 months, median 4 months) after showing either response or stable disease to carboplatin, were treated with ifosfamide (5 g/m2 intravenously over 24 h, day 1) and carboplatin (200 mg/m2 intravenously day 2) as second-line treatment. The mean number of treatment cycles was 3.5 (range 1-6). The major toxicities were thrombocytopenia (WHO grade 3/4, 25%), neutropenia (WHO grade 3/4, 40%) and encephalopathy (WHO grade 3/4, 15%). Overall response rate was 15% [complete response, 0; partial response, 3 (15%); no change, 5 (25%) and progressive disease, 12 (60%)]. The median survival from the date of second-line treatment was 7 months. This combination offers no advantage over either agent used alone.     

Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis

BACKGROUND: In the previous meta-analysis of dose intensity (dosage) of chemotherapy in advanced ovarian cancer, we analyzed data on cyclophosphamide, altretamine (hexamethylmelamine), doxorubicin, and cisplatin. Only cisplatin showed statistically significant association of complete and partial clinical response with dose intensity. PURPOSE: This analysis updates the previous results and further characterizes response to cisplatin alone or in multiagent regimens. METHODS: We analyzed data from 18 regimens containing platinum (cisplatin or carboplatin) that were used in nine new randomized trials, in addition to data from the 60 groups of patients in our previous study in which responses were reported. Relative dose intensity was calculated as a fraction of the dosage of a drug in the standard regimen of cyclophosphamide, altretamine, doxorubicin, and platinum (CHAP). We performed single and multiple regression analyses to determine the relationship between disease outcome and relative dose intensity for cyclophosphamide, platinum, and doxorubicin alone or in combination. RESULTS: The association between outcome and dose intensity for platinum alone or in multiagent regimens was statistically significant. This association was of borderline significance for cyclophosphamide alone but was not significant for this drug in multiagent regimens. There were insufficient data to test the relationship for doxorubicin as a single agent, but in multiagent regimens, the relationship was borderline (P = .05). Multiagent regimens containing platinum produced greater response rates than platinum alone for any fixed, planned relative dose intensity for platinum. CONCLUSIONS: Our results support other published findings that use of cyclophosphamide and doxorubicin increases the efficacy of single-agent platinum. Relative dose intensity values for cyclophosphamide used alone were larger than those used in multiagent regimens, which might explain why the relationship between relative dose intensity and outcome for cyclophosphamide was not significant for use in multiagent regimens. Similarly, none of the multiagent regimens incorporated doxorubicin at a relative dose intensity for which the drug is found to be effective as a single agent. IMPLICATIONS: Prospective clinical trials are required to test the effect of higher relative dose intensity for doxorubicin and cyclophosphamide added to platinum in advanced ovarian cancer. An important element in the design of prospective trials will be to test for the relative importance of dose intensity versus total dose. This testing is best achieved in a three-arm study design such as that reported in adjuvant treatment of stage II breast cancer conducted by the Cancer and Leukemia Group B.     

Fractionated high dose rate intraluminal brachytherapy in palliation of advanced esophageal cancer

PURPOSE: To optimize the dose of fractionated brachytherapy for palliation of advanced esophageal cancer. METHODS AND MATERIALS: One hundred and seventy-two patients with advanced esophageal cancer were randomized to receive 12 Gy/2 fractions (group A); 16 Gy/2 fractions (group B), and 18 Gy/3 fractions (group C) by high dose rate intraluminal brachytherapy (HDRILBT). Treatment was given weekly and dose prescribed at 1 cm from the source axis. Patients were followed up monthly and assessed for dysphagia relief and development of complications. RESULTS: Twenty-two patients died before completing treatment due to advanced disease and poor general condition. The overall survival was 19.4% at the end of 12 months for the whole group (A--9.8%, B--22.46%, C--35.32%; p > 0.05). The dysphagia-free survival was 28.9% at 12 months for the whole group (A--10.8%, B--25.43%, C--38.95%; p > 0.05). Forty-three patients developed fibrotic strictures needing dilatation (A--5 of 35, B--15 of 60, C--23 of 55; p = 0.032). Twenty-seven patients had persistent luminal disease (A--11, B--6, C--10), 15 of which progressed to fistulae (A--7, B--2, C--6; p = 0.032). There was no effect of age, sex, race, histology, performance status, previous dilation, presenting dysphagia score, presenting weight, grade, tumor length, and stage on overall survival, dysphagia-free, and complication-free survival (p > 0.05). On a multivariate analysis, brachytherapy dose (p = 0.002) and tumor length (p = 0.0209) were found to have a significant effect on overall survival; brachytherapy dose was the only factor that had an impact on local tumor control (p = 0.0005), while tumor length was the only factor that had an effect on dysphagia-free survival (p = 0.0475). When compared to other forms of palliation currently available (bypass surgery, laser, chemotherapy, intubation, external radiotherapy), fractionated brachytherapy gave the best results with a median survival of 6.2 months. CONCLUSIONS: Fractionated brachytherapy is the best modality for palliation of advanced esophageal cancer. It offers the best palliation to patient when compared to all other modalities currently available. The optimal brachytherapy dose ranges between 16 Gy in two fractions and 18 Gy in three fractions given a week apart.     

First-line treatment of advanced nonsmall cell lung carcinoma with docetaxel and vinorelbine

BACKGROUND: Docetaxel and vinorelbine are active agents in the treatment of nonsmall cell lung carcinoma (NSCLC). The efficacy and toxicity of this combination was evaluated in a Phase II study in patients with advanced NSCLC. METHODS: Forty-six chemotherapy-naive patients (44 men and 2 women with a median age of 64 years) with NSCLC (11 with Stage IIIB and 35 with Stage IV disease) were entered into the study; the World Health Organization (WHO) performance status was 0, 1, and 2 in 32, 11, and 3 patients, respectively. Patients received vinorelbine (25 mg/m2) on Day 1 and docetaxel (100 mg/m2) on Day 2 in cycles repeated every 3 weeks. Granulocyte-colony stimulating factor was given to all patients from Day 3 to Day 10. RESULTS: One hundred and seventy-seven courses of chemotherapy were administered. Adverse events included WHO Grade 4 neutropenia (15 patients), Grade 3/4 thrombocytopenia (3 patients), Grade 3 anemia (2 patients), Grade 2 and 3 neurotoxicity (7 patients and 1 patient, respectively), and Grade 3 fatigue (2 patients). Twenty patients (43%) required hospitalization: 11 (24%) for neutropenic fever (2 deaths from sepsis), and 9 (20%) for nonneutropenic pulmonary infections (2 deaths from cardiopulmonary insufficiency). The median overall survival was 5 months and the 1-year survival was 24%. Four complete responses (9.8%) and 11 partial responses (26.8%) (overall response rate of 36.6%; 95% confidence interval, 21.8-51.3%) were documented in 41 evaluable patients (intent-to-treat: 32.6%). Stable and progressive disease occurred in 13 patients each (31.7%). The median duration of response was 5 months and the median time to progression was 3 months (6 months for the responders). CONCLUSIONS: This schedule of docetaxel and vinorelbine combination is effective but its relatively high incidence of complicated neutropenia precludes its general use in patients with advanced NSCLC.     

Age, pain intensity, and opioid dose in patients with advanced cancer

BACKGROUND: Elderly patients are more likely to be affected by the acute and chronic toxicities of opioids, but an association between age and long term opioid consumption has not been established clearly in patients with advanced cancer. METHODS: The computerized records of 197 cancer patients admitted to a palliative care unit in Edmonton, Alberta, Canada were examined. The authors examined: demographics (age, gender, and location of primary tumor), pain characteristics (presence of neuropathic pain and incidental pain), mean daily pain intensity (MDPI), and daily opioid consumption measured as (parenteral) morphine equivalent daily dose (MEDD). MDPI and MEDD were assessed on Days 2 and 7 after admission, on the day of maximum opioid consumption, and on the day of maximum pain intensity during admission. Average values for MDPI and MEDD were calculated between Days 2 and 7. RESULTS: When age was treated as a categoric variable (< 65 years, 65-74 years, and 75+ years), statistically significant differences in MEDD were observed for age for all estimates except those for Day 7, with older patients requiring a lower equianalgesic dose. No major differences were observed for pain intensity and for the presence of incidental or neuropathic pain across the different age groups. In the multivariate analysis, the reduction in MEDD ranged between 27-71 mg when patients age > or = 75 years were compared with younger adults. A MEDD increase that ranged between 82-137 mg was associated with the presence of neuropathic pain. CONCLUSIONS: The current study suggests that elderly cancer patients may experience a similar level of pain intensity but require a lower amount of opioid analgesia than younger adults. However, because elderly patients are more likely to be affected by the acute and chronic toxicities of opioids, opioids should be initially administered at a lower dose and titrated cautiously in these patients.     

Adjuvant 32P in the treatment of ovarian carcinoma

The purpose of this study was to evaluate the efficacy of adjuvant 32P for patients with high-risk, early-stage ovarian carcinoma. Twenty-five patients underwent apparent complete resection followed by 32P (15 mCi) at the University of Florida between 1976 and 1993. Minimum and median follow-up times were 3 and 8 years, respectively. The rate of local control at 10 years was 83%. Four of the 5 patients who experienced recurrent disease had a component of intra-abdominal disease at the time of relapse. The absolute and cause-specific survival rates at 10 years were 68% and 82%, respectively. There were no severe acute complications. Five patients experienced significant late complications, including chronic abdominal cramping that was treated conservatively (3 patients) and small bowel obstruction necessitating surgical intervention (2 patients). Adjuvant 32P results in disease control and survival rates that are similar to those observed after adjuvant chemotherapy. However, the risk of late complications, particularly small bowel obstruction, is higher.