Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT.

BACKGROUND: Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. DESIGN AND METHODS: We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling. RESULTS: Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea. CONCLUSION: Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected. CLINICALTRIALS.GOV: NCT00066690 and NCT00066703.

Altered insulin response to glucose in weight-losing cancer patients.

Cancer cachexia and the underlying metabolic disturbances are due in part to either altered insulin release and action. Glucose intolerance in cancer patients is frequently observed but the nature of the insulin response is not usually described. The aim of this study was to investigate the insulin response in fasted, weigh-losing cancer patients following an oral glucose load (75 g). All cancer patients (n = 35) showed glucose intolerance. Three types of response were identified; those with an increased insulin: glucose ratio (I:G) at 60 min, (average 12.3, n = 13), those with a normal I:G (average 7.2 n = 7) and those with a decrease I:G (average 4.2, n = 15). Fasting plasma glucose concentrations were normal in all groups prior to the glucose tolerance test. However, patients with the lowest I:G also had the lowest fasting plasma insulin concentrations, the lowest plasma albumin concentrations and the highest plasma triglyceride concentrations. Those patients with an abnormal insulin response (either high or low I:G) had significantly greater weight loss (16% for low I:G group, 13% for the high I:G) compared to the normal responders (8%). Plasma fatty acid concentrations were increased in all cancer patients and decreased appropriately after glucose administration, indicating that lipolysis remained sensitive to the action of insulin. It is concluded that weight loss in cancer is associated with glucose intolerance and an abnormal insulin response, and that this response is indicative of either insulin resistance (high I:G) or decreased pancreatic function (low I:G). These findings suggest a role for insulin replacement therapy in the latter group of patients.

Non-haematological toxicity limiting the application of sequential high dose chemotherapy in patients with advanced breast cancer.

A programme of repeated high dose chemotherapy for advanced breast cancer was developed using (1) cyclophosphamide 4 g/m2 followed by autologous peripheral blood stem cell (PBSC) collection; (2) three cycles of conventional dose chemotherapy; (3) high dose cyclophosphamide, cisplatin, and carmustine with PBSC rescue; and (4) high dose etoposide and melphalan with PBSC rescue. Fifteen eligible patients had advanced poor prognosis breast cancer either at initial diagnosis (one patient) or at relapse (14 patients). During the course of the protocol, there were three treatment related deaths, two patient withdrawals due to debilitating toxicity, five patient withdrawals due to disease progression, and one patient withdrawal due to inadequate collection of PBSC. The remaining four patients did not complete the planned protocol as the programme was terminated because of the unacceptable morbidity and mortality. They were treated with an alternative high dose chemotherapy protocol which was well tolerated. This study highlights the significant problems associated with a complex sequential high dose chemotherapy regimen. Cyclophosphamide mobilized PBSC infused following high dose chemotherapy enables rapid haematological recovery. However the non-haematological toxicity following high dose chemotherapy regimens is often severe and may limit the application of certain sequential high dose chemotherapy combinations in patients with breast cancer.

Adjuvant chemoimmuno- and immunotherapy in Dukes' stage B2 and C colorectal carcinoma: a 7-year follow-up analysis.

A prospectively randomised controlled clinical trial of adjuvant therapy was undertaken, at a single-centre, population-based cancer institute, in patients with Dukes' stages B2 and C colorectal carcinoma after curative surgery. Between 1976 and 1983, 253 patients were randomised to either control (no further therapy after surgery), immunotherapy (oral bacille Calmette-Guérin [BCG] 120 mg once a month) for 5 years or chemoimmunotherapy (oral BCG as above with methyl-cyclohexyl-chloroethyl nitrosourea [meCCNU] 130 mg/m2 on day 1 and 5-fluorouracil [5-FU] 325 mg/m2/day on days 1-5 and 375 mg/m2/day on days 36-40) repeated every 10 weeks for 8 cycles. The median follow-up of patients is now 6.95 years. Of the control, immunotherapy, and chemoimmunotherapy groups 22.35%, 39.28%, and 28.57%, respectively, have relapsed. The log-rank analysis of results shows no disease-free or overall survival advantage for patients receiving adjuvant therapy compared with the control group. Patients receiving adjuvant immunotherapy for stage B2 appear to have a significantly inferior disease-free survival compared with other groups, but their overall survival is similar. There are no significant differences in disease-free or overall survival in the three groups of patients with stage C tumour. Of 82 patients dying, 78.05% died of progressive colorectal carcinoma, 13 patients developed a second malignancy; the remainder died of seemingly unrelated causes.

Peripheral carcinoid tumours of the lung: a clinicopathological study.

Peripheral carcinoid tumours (PCT) of the lung are a distinct entity. These tumours arise from subsegmental or distal bronchioles, are usually well circumscribed and encapsulated, and contain varying amounts of spindle cells. Their histogenesis is from the Kultchitsky or neurosecretory type of cells. Of 52 patients with carcinoid tumours of the lung, 11 (21.1%) had PCT. The mean age was 60.2 years, 9 out of 11 patients were females, and about two-thirds of tumours were in the left lung (8 out of 13). No patient developed carcinoid syndrome, but three patients had nonspecific respiratory symptoms. Bronchoscopy was not helpful in diagnosing any of these cases. Four patients required a wedge resection of the lung; the other six underwent lobectomy. One patient had tumours detected incidentally at autopsy. Mean tumour size was 2.39 cm (range 1.0-5.0 cm); four tumours were 3.0 cm or larger in diameter. Three cases (27.3%) had regional lymph node metastases, but no systemic metastasis was discovered. Apart from the patient who was discovered to have carcinoid tumours at autopsy, all others are alive and disease-free from 1 to 6 years after surgery.

Lymphography and computed tomography in lymph node metastases from malignant melanoma.

Contrast lymphography and regional computed tomography (CT) were performed prior to lymph node dissection in 49 patients with clinical suggestion of lymph node metastases from malignant melanoma. The overall specificity and sensitivity for lymphography was 62% and 70%, respectively, and for CT 83% and 70%, respectively. There was 67% concordance of the radiologic reports. The combined modality sensitivity and specificity were 79% and 84%, respectively. Clinical lymph node examination was poor in accurately diagnosing lymph node involvement with melanoma (42% true positive, 58% false positive). Lymphography produced too many false negative and false positive reports to be of value in detecting lymph node metastases on its own. CT was slightly superior to lymphography in correctly predicting the lymph node status of the upper extremity. The present clinical and radiologic techniques would seem to be inadequate for detecting lymph node metastases in malignant melanoma.

Natural human interferon-beta in metastatic malignant melanoma. A phase II study.

A phase II trial of natural human fibroblast interferon (HuIFN-beta) in 15 previously untreated patients with advanced metastatic malignant melanoma is reported. It was given as out-patient treatment by 30 min i.v. infusion of 60 x 10(6) U/m2/day on 4 consecutive days each week. Systemic toxicity was acceptable to all patients except one who declined further treatment. Performance status of treated patients was good. Three patients had a partial response and 3 patients had stable disease. The median time to response was 13.3 weeks and the duration of response was 22.6 weeks. Responses were seen in lungs and soft tissues only and relapses were seen particularly in the central nervous system and the liver. Overall survival of the patients was only 20.7 weeks. Those who achieved a partial remission had a median survival of 34.7 weeks and those with disease stabilisation a survival of 22.0 weeks. HuIFN-beta is shown to have anti-tumour activity in advanced metastatic melanoma, although the unit dose of HuIFN-beta is much larger than that required to achieve similar anti-tumour activity with interferon-alpha.

The syndrome of inappropriate antidiuretic hormone secretion with carcinoma of the tongue.

A 64-year-old male developed symptomatic recurrent syndrome of inappropriate ADH secretion in association with locally advanced squamous cell carcinoma of the tongue. His SIADH was managed successfully with saline infusion, frusemide, and maintenance treatment with demeclocycline.

An unusual case of renal cancer showing mixed tumor response to interferon.

A patient with renal cell carcinoma, recurrent in the renal bed and metastatic to the lung parenchyma, hilar lymph nodes, and ilium bone, showed a complete response to 12 months of treatment with human diploid fibroblast interferon. However, concurrently with clinical and pathologic resolution of the metastatic and recurrent tumor at known sites, a brain metastasis developed, which was not clinically or radiologically apparent during his lifetime. At autopsy, there was no evidence of metastatic renal cell carcinoma at the known sites of disease. In the brain, there was a massive fresh intracerebral hemorrhage originating in a small focus of metastatic renal cell carcinoma. Possible explanations for these mixed responses to interferon and this curious phenomenon are discussed.

Nocardia infection in splenectomized patients: case reports and a review of the literature.

Opportunistic infections are increasingly becoming a problem in cancer patients amongst whom infection with Nocardia species is particularly difficult to detect due to the capricious natural history of the disease. Three cases of Nocardia infection in patients who had undergone splenectomy for haematological malignancy are presented. These cases illustrate the diverse mode of presentation, the natural history and the difficulties in early and accurate diagnosis of Nocardia infection. Despite the difficulties in arriving at the correct diagnosis, these cases highlight the importance of early institution of appropriate antibiotic therapy. Antibiotics should be given in adequate doses to control the initial infection and be maintained for a prolonged period to prevent relapses.

Adjuvant chemoimmunotherapy after regional lymphadenectomy for malignant melanoma.

Thirty patients with malignant melanoma metastatic to regional lymph nodes who underwent either a full or partial node dissection were treated with adjuvant chemoimmunotherapy (CIT). In this pilot study, 11 patients were given intravenous (i.v.) DTIC plus intradermal (i.d.) BCG (D/BCG), 19 patients received i.v. DTIC, BCNU, and hydroxyurea plus oral BCG (DBH/BCG). Their overall survival (OS) and disease-free interval (DFI) following node dissection and CIT were compared with 33 historical control (HC) patients from the preceding 4 years, matched for the known prognostic factors in melanoma. The D/BCG group received a median of five courses, the DBG/BCG group six courses. Minimum follow-up of all patients is in excess of 7 years. No significant differences were observed in either DFI or OS from diagnosis between the two treatment groups or between CIT patients and HC patients. A highly significant difference was observed in DFI and OS in favor of the partial node dissection (PND) group when compared with full node dissection (FND) group. No other known variables in the PND group accounting for their improved survival are noted. Five patients in DBH/BCG and three in D/BCG group are still alive 84-114 months after completing therapy.

Pulmonary sarcoidosis following interferon therapy for advanced renal cell carcinoma.

A 57-year-old woman developed pulmonary sarcoidosis during therapy with interferon beta for advanced renal cell carcinoma metastatic to mediastinal lymph nodes. The possible role of interferon beta in the pathogenesis of sarcoidosis in this patient is discussed.

Combination of fibroblast interferon (HuIFN beta), carboxamide (DTIC), and cimetidine for advanced malignant melanoma.

In vitro synergism between interferons (IFNs) and chemotherapeutic drugs has been demonstrated, and an enhancement of IFN's antiproliferative effects when combined with cimetidine has been suggested in melanoma patients. In this pilot study, 12 patients with advanced malignant melanoma received HuIFN beta by 30 min i.v. infusion at 30 X 10(6) u/m2 day for 4 days, followed by i.v. decarbazine (DTIC) 1.0 g/m2 on day 5, repeated every 4 weeks. Oral cimetidine, 300 mg q.i.d., was given continuously. All the patients had visceral (bulky) metastases. No objective responses were observed; however, two patients had stable diseases for 16 and 20 weeks, respectively. Mild chills and fever with IFN, and mild to moderate emesis with DTIC, were noted. No additive haemopoietic or hepatic toxicity was observed. Combination of HuIFN beta, DTIC, and cimetidine is relatively nontoxic, but does not appear to have a significant antitumor activity in patients with advanced malignant melanoma.

Auto-immune thrombocytopenia related to interferon therapy.

A patient with renal cell carcinoma developed reversible autoimmune thrombocytopenia while receiving leukocyte interferon (IFN) and subsequently fibroblast IFN. Bone marrow biopsies and elevated platelet-associated IgG were suggestive of immune thrombocytopenia. The patient's history of exposure to IFN and exclusion of other causes are most consistent with drug-induced immune thrombocytopenia. Rechallenge with acetaminophen, the only other drug the patient was receiving concurrently, failed to induce thrombocytopenia. With IFN alpha, acute thrombocytopenia resolved within 48 h, whereas after IFN beta it was 5 wk before platelet counts returned to normal. PaIgG, however, remained elevated for up to 30 wk. Sensitive in vitro tests failed to confirm drug-dependent binding of IgG to the patient's platelets. It is suggested that this patient developed interferon-induced autoimmune thrombocytopenia.

Extended phase I study of human beta-interferon in human cancer.

Ten patients with advanced cancer were treated with weekly intravenous escalating doses of human beta-interferon (HuIFN beta) 4 days each week. The starting dose of HuIFN beta was 3.0 X 10(6) units/m2 and the dose was doubled each week until dose-limiting toxicity was observed. Subjective toxicity included mild fevers and chills, malaise and flu-like symptoms. The lowest dose which caused suppression of the platelet and/or white cell count was 64 X 10(6) units daily, and the maximum dose given was 320 X 10(6) units daily. Both subjective and objective toxicity were not dose-related, easily managed and reversible. Serum interferon levels and the duration of measurable interferon activity on natural killer cells was in general dose-dependent. Two patients had an objective partial response, and two others showed stable disease while receiving HuIFN beta.

Radioiodinated peanut lectin: clinical use as a tumour-imaging agent and potential use in assessing renal-tubular function.

Peanut lectin (PNA) has been shown to have a high affinity for Thomsen-Friedenreich (T) antigen, which is associated with the membrane of many solid tumour cells. PNA labelled with 131I was used as a tumour-imaging substance in patients with known metastatic cancer. Serial gamma scintiscans were obtained in 17 patients following a single injection of 131I-labelled PNA. Only in 1 patient was this technique able to reveal a known metastasis at analogue imaging. In the remaining patients, no visible uptake of 131I-PNA could be demonstrated at sites of known metastases. PNA is rapidly excreted through the kidneys and localizes in the renal tubules. As a tumour-imaging agent, 131I-PNA appears to be without value, but its renal-excretory characteristics make it a potentially useful agent for the in vivo assessment of renal-tubular disorders.