The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials.

AIM: To report on the multidisciplinary approach, focusing specifically on the role of the interventional radiologist (IR), used to support the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 trials. MATERIALS AND METHODS: Patients who underwent percutaneous image-guided biopsy for the BATTLE and BATTLE-2 trials were reviewed. A radiology-based, three-point, lesion-scoring system was developed and used by two IRs. Lesions were given a score of 3 (most likely to yield sufficient material for biomarker analysis) if they met the following criteria: size >2 cm, solid mass, demonstrated imaging evidence of viability, and were technically easy to sample. Lesions not meeting all four criteria were scored 2 with the missing criteria noted as negative factors. Lesions considered to have risks that outweighed potential benefits receive a score of 1 and were not biopsied. Univariate and multivariate analyses were performed to evaluate the score's ability to predict successful yield for biomarker adequacy. RESULTS: A total of 555 biopsies were performed. The overall yield for analysis of the required biomarkers was 86.1% (478/555), and 84% (268/319) and 88.9% (210/236) for BATTLE and BATTLE-2, respectively (p=0.09). Lesions receiving a score of 3 were adequate for biomarker analysis in 89% of cases. Lesions receiving a score of 2 with more than two negative factors were adequate for molecular analysis in 69.2% (IR1, p=0.03) and 74% (IR2, p=0.04) of cases. The two IRs scored 78.4% of the lesions the same indicating moderate agreement (kappa=0.55; 95% confidence interval [CI]: 0.48, 0.61). CONCLUSIONS: IRs add value to clinical trial teams by optimising lesions selected for biopsy and biomarker analysis.

Weekly paclitaxel, carboplatin, cetuximab, and cetuximab, docetaxel, cisplatin, and fluorouracil, followed by local therapy in previously untreated, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The survival advantage of induction chemotherapy (IC) followed by locoregional treatment is controversial in locally advanced head and neck squamous cell carcinoma (LAHNSCC). We previously showed feasibility and safety of cetuximab-based IC (paclitaxel/carboplatin/cetuximab-PCC, and docetaxel/cisplatin/5-fluorouracil/cetuximab-C-TPF) followed by local therapy in LAHNSCC. The primary end point of this phase II clinical trial with randomization to PCC and C-TPF followed by combined local therapy in patients with LAHNSCC stratified by human papillomavirus (HPV) status and T-stage was 2-year progression-free survival (PFS) compared with historical control. PATIENTS AND METHODS: Eligible patients were ≥18 years with squamous cell carcinoma of the oropharynx, oral cavity, nasopharynx, hypopharynx, or larynx with measurable stage IV (T0-4N2b-2c/3M0) and known HPV by p16 status. Stratification was by HPV and T-stage into one of the two risk groups: (i) low-risk: HPV-positive and T0-3 or HPV-negative and T0-2; (ii) intermediate/high-risk: HPV-positive and T4 or HPV-negative and T3-4. Patient reported outcomes were carried out. RESULTS: A total of 136 patients were randomized in the study, 68 to each arm. With a median follow up of 3.2 years, the 2-year PFS in the PCC arm was 89% in the overall, 96% in the low-risk and 67% in the intermediate/high-risk groups; in the C-TPF arm 2-year PFS was 88% in the overall, 88% in the low-risk and 89% in the intermediate/high-risk groups. CONCLUSION: The observed 2-year PFS of PCC in the low-risk group and of C-TPF in the intermediate/high-risk group showed a 20% improvement compared with the historical control derived from RTOG-0129, therefore reaching the primary end point of the trial.

Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Enhanced phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key adaptive changes accounting for epidermal growth factor receptor (EGFR) inhibitor-resistant growth in head and neck squamous cell carcinoma (HNSCC). We designed a phase II clinical trial of EGFR tyrosine kinase inhibitor (TKI), erlotinib, in association with the mTOR inhibitor, everolimus, based on the hypothesis that the downstream effects of Akt through inhibition of mTOR may enhance the effectiveness of the EGFR-TKI in patients with recurrent/metastatic HNSCC. PATIENTS AND METHODS: Patients with histologically or cytologically confirmed platinum-resistant HNSCC received everolimus 5 mg and erlotinib 150 mg daily orally until disease progression, intolerable toxicity, investigator or patient decision. Cytokines and angiogenic factors profile, limited mutation analysis and p16 immunohistochemistry status were included in the biomarker analysis. RESULTS: Of the 35 assessable patients, 3 (8%) achieved partial response at 4 weeks, 1 confirmed at 12 weeks; overall response rate at 12 weeks was 2.8%. Twenty-seven (77%) patients achieved disease stabilization at 4 weeks, 11 (31%) confirmed at 12 weeks. Twelve-week progression-free survival (PFS) was 49%, median PFS 11.9 weeks and median overall survival (OS) 10.25 months. High neutrophil gelatinase lipocalin (P = 0.01) and vascular endothelial growth factor (VEGF) (P = 0.04) plasma levels were significantly associated with worse OS. CONCLUSIONS: The combination of erlotinib and everolimus did not show significant benefit in unselected patients with platinum-resistant metastatic HNSCC despite a manageable toxicity profile. Markers of tumor invasion and hypoxia identify a group of patients with particularly poor prognosis. CLINICAL TRIAL NUMBER: NCT00942734.

A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†.

BACKGROUND: KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. PATIENTS AND METHODS: Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. RESULTS: One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. CONCLUSION: Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01362296.

Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: We evaluated combined targeting with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: The combination was studied in human endothelial cells and head and neck and lung cancer xenograft model systems. Patients with recurrent or metastatic SCCHN were treated with weekly cetuximab and bevacizumab, 15 mg/kg on day 1 given intravenously every 21 days, until disease progression. Analysis of tumor biomarkers and related serum cytokines was performed. RESULTS: Cetuximab plus bevacizumab enhanced growth inhibition both in vitro and in vivo, and resulted in potent reduction in tumor vascularization. In the clinical trial, 46 eligible patients were enrolled. The objective response rate was 16% and the disease control rate 73%. The median progression-free survival and overall survival were 2.8 and 7.5 months, respectively. Grade 3-4 adverse events were expected and occurred in less than 10% of patients. transforming growth factor alpha, placenta-derived growth factor, EGFR, VEGFR2 increased and VEGF decreased after treatment but did not correlate with treatment efficacy. CONCLUSIONS: Cetuximab and bevacizumab are supported by preclinical observations and are well tolerated and active in previously treated patients with SCCHN.

A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC).

BACKGROUND: Combined inhibition of vascular, platelet-derived, and epidermal growth factor receptor (EGFR) pathways may overcome refractoriness to single agents in platinum-pretreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This randomized, double-blind, multicenter, phase II trial evaluated sunitinib 37.5 mg/day plus erlotinib 150 mg/day versus placebo plus erlotinib continuously in 4-week cycles. Eligible patients had histologically confirmed stage IIIB or IV NSCLC previously treated with one or two chemotherapy regimens, including one platinum-based regimen. The primary end point was progression-free survival (PFS) by an independent central review. RESULTS: One hundred and thirty-two patients were randomly assigned, and the median duration of follow-up was 17.7 months. The median PFS was 2.8 versus 2.0 months for the combination versus erlotinib alone (HR 0.898, P = 0.321). The median overall survival (OS) was 8.2 versus 7.6 months (HR 1.066, P = 0.617). Objective response rates (ORRs) were 4.6% and 3.0%, respectively. Sunitinib plus erlotinib was fairly well tolerated although most treatment-related adverse events (AEs) were more frequent than with erlotinib alone: diarrhea (55% versus 33%), rash (41% versus 30%), fatigue (31% versus 25%), decreased appetite (30% versus 13%), nausea (28% versus 14%), and thrombocytopenia (13% versus 0%). CONCLUSIONS: The addition of sunitinib to erlotinib did not significantly improve PFS in patients with advanced, platinum-pretreated NSCLC.

A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel-carboplatin (CP) plus motesanib or bevacizumab. PATIENTS AND METHODS: Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs). RESULTS: ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C(max) and C(min) values were consistent with its pharmacokinetic properties observed in previous studies. CONCLUSIONS: The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study.

Effect of diethylaminoethyl-dextran on colony formation of human tumor cells in semisolid suspension cultures.

The effect of diethylaminoethyl-dextran on colony formation of established and primary human ovarian and breast tumor cells in semisolid suspension cultures was investigated. At the concentration of 250 to 300 micrograms/ml used in the human tumor stem cell assay, diethylaminoethyl-dextran inhibited in vitro growth of 3 of 4 human breast tumor cell lines and of 10 of 19 primary tumors. It did not affect growth in 7 primary tumors and enhanced colony formation in 2 tumors. We suggest that diethylaminoethyl-dextran may interact in the human tumor stem cell assay with other sites additional to sulfuric acid residues of the agar and that these effects may cancel or outweigh its purported beneficial effects.

Aminoglutethimide after tamoxifen therapy in advanced breast cancer: M. D. Anderson Hospital experience.

Forty-six patients with progressive metastatic disease following initial response to tamoxifen therapy were treated with aminoglutethimide. Three patients (6%) achieved complete remission, 15 patients (33%) had partial response, and eight patients (17%) had stable disease. Twenty patients (44%) had progressive disease. The most common side effects were transient skin rash, lethargy, or dizziness. In four patients (7%), treatment was discontinued because of undesirable side effects within the first 2 weeks of the study. These data show that aminoglutethimide is an effective agent following tamoxifen therapy.

Normalization of in vitro sensitivity testing of human tumor clonogenic cells.

The use of normal bone marrow (granulocyte-macrophage colony-forming units) as a point of reference to normalize the in vitro activities of anticancer agents has been investigated. The cytotoxic effects of four substituted anthraquinone derivatives, and of vinblastine on myeloid progenitors of different donors were reproducible up to a cell kill of approximately 60%. Equitoxic in vitro concentrations for normal bone marrows did not correlate with in vivo pharmacokinetic concentrations of these drugs. Breast tumor progenitor cells of 46 specimens were more sensitive than were bone marrow progenitors to the anthraquinone derivatives in 26 to 39% of instances, ratios which are similar to the clinically observed response rates of patients with breast carcinoma to these agents. Tumors were either sensitive or resistant to all four drugs in 68% (10 tumors were more sensitive, and 21 tumors were less sensitive than normal bone marrow); but in 32% of instances there were differences in tumor sensitivity for the four drugs, and the assay could select one to three drugs for which the tumor sensitivity was greater than that of bone marrow. Correlations of in vitro sensitivity and of clinical response to single agent treatments were determined in 21 patients, and the concordance was 71%. The value of the assay in predicting clinical response ranked best for sensitivity determinations within the normalized dose ranges, when testing within three different dose ranges was compared in a group of six patients. The concordance was higher in the small (1 or 2 metastatic sites) than in the large (greater than or equal to 3 metastatic sites) tumors (85 versus 50%), indicating a confounding influence of tumor load on the ability of the assay to predict efficacy of treatment. A rule of thumb is proposed for altering the in vitro sensitivity test results for large tumors that improves the overall concordance to 90%.

Pathological assessment of response to induction chemotherapy in breast cancer.

Macroscopic and microscopic pathology review was used to assess the degree of tumor reduction after preoperative chemotherapy in 90 patients with inflammatory and locally advanced breast cancer. Fifteen (17%) patients had no evident residual macroscopic tumor on gross pathological examination, and 6 of these 15 had no residual tumor on microscopic review either. There was no significant difference in disease-free and overall survival between the six patients with no microscopic disease and the nine patients with only microscopic residual disease but no residual macroscopic tumor. These 15 patients with major reduction after induction chemotherapy had a longer disease-free survival (DFS) (median not reached at 5 yr) than the other 75 patients with lesser degrees of tumor reduction (DFS = 22 mo; P less than 0.01). Clinical evaluation of response to chemotherapy was a less accurate predictor of outcome than was the pathological assessment of response. Complete clinical responders had a 4-yr DFS of 55%, whereas patients with non macroscopic residual tumor following preoperative chemotherapy, less than one-half of whom had been judged to be a complete clinical responder, had a median DFS of greater than 60 mo and a 4-yr DFS of 75%. Patients whose mastectomy specimen had no macroscopic residual disease had a 93% 5-yr survival compared to patients with a less marked response to therapy who had a 5-yr survival of 30% (P less than 0.01). No pretreatment patient or tumor-related variables correlated with the degree of tumor reduction following preoperative therapy. Achievement of a mastectomy specimen free of residual macroscopic tumor after preoperative chemotherapy is an excellent prognostic factor for a prolonged DFS and survival. This information should be considered in the selection of postoperative systemic therapy.

Prognostic factors in metastatic breast cancer treated with combination chemotherapy.

Six hundred nineteen patients with metastatic breast cancer, treated with a combination of 5-fluorouracil, Adriamycin, and cyclophosphamide, or close variations of this program, with or without immunotherapy were analyzed retrospectively to identify those host, tumor, or treatment characteristics that might be of prognostic importance in predicting response to chemotherapy and survival from onset of the 5-fluorouracil-Adriamycin-cyclophosphamide treatments. Primary tumor characteristics such as size of primary, number of axillary nodes involved, stage at diagnosis, and type of surgery used for primary treatment were not found to be of prognostic significance. Host characteristics such as age, menstrual status, or family history of breast cancer were similarly unrelated to outcome. Non-Caucasian patients had a lower response rate and somewhat shorter survival than did Caucasians. Pretreatment weight loss, poor performance status, and abnormal biochemical and hematological values were of adverse prognostic significance. An estimate of total extent of disease based on criteria for rating extent of involvement at 12 potential sites was a much more important prognostic factor related to response and survival than actual sites of involvement or the traditional "dominant site" classification. There was a trend, however, for patients with bone involvement to have a longer survival than did patients with metastases to other organ sites. Shorter survival times were observed among patients exposed to extensive prior radiotherapy and those who failed to respond to prior hormonal treatment. The prognostic variables identified in this paper should be used for the design and comparison of clinical trials in the future.

Bisantrene, an active new drug in the treatment of metastatic breast cancer.

Forty-four patients with metastatic breast cancer who had previously received extensive conventional systemic therapy, including combination chemotherapy with doxorubicin, were treated with Bisantrene, a new anthracene derivative. The dose schedule was 250 to 300 mg/sq m body surface administered as a 1- to 2-hr i.v. infusion. Of 40 evaluable patients, there were nine partial responses, and 18 patients had stable disease. Responses were seen in all major sites of organ involvement with a median time to progression of 28 weeks. Moreover, responses were seen among patients who had either failed to respond or had demonstrated refractoriness to prior therapy with doxorubicin, suggesting an apparent lack of cross-resistance between doxorubicin and Bisantrene. Except for myelosuppression and one incidence of acute anaphylactoid reaction, Bisantrene was generally well tolerated by most patients. We believe that Bisantrene may ultimately have a major role in the effective treatment of metastatic breast cancer, and further clinical trials are warranted.

Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: a prospective randomized study.

Fifty-nine evaluable patients under 65 years of age with measurable metastatic breast cancer and without prior chemotherapy were randomly assigned to treatment with fluorouracil, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (FAC) at standard or high doses (100% to 260% higher than standard FAC) following a dose escalation schedule. Patients randomized to the high-dose FAC received the first three cycles of therapy within a protected environment. Subsequent cycles for this group were administered at standard doses of FAC in an ambulatory setting, the same as for the control group. After reaching 450 mg/m2 of Adriamycin, patients in both groups continued treatment with cyclophosphamide, methotrexate, and fluorouracil until there was disease progression. Analysis of pretreatment patient characteristics showed an even distribution for most known pretreatment factors, although the control group had slightly (but nonsignificantly) more favorable prognostic characteristics. Fourteen patients (24%) achieved a complete remission (CR) and 32 (54%) achieved a partial remission (PR), for an overall major response rate of 78%. There were no differences in overall, CR, or PR rates between the high-dose FAC and control groups. The median response durations were 11 and 10 months for the protected environment and control groups, respectively, and the median survival was 20 months for both groups. Hematologic, gastrointestinal (GI), and infection-related complications were significantly more frequent and severe in the group treated with high-dose chemotherapy. Stomatitis, diarrhea, and skin toxicity were dose-limiting. However, there were no treatment-related deaths. High-dose induction combination chemotherapy with the agents used in this study failed to increase the response rate or survival duration, and resulted in a substantial increase in toxicity.

High-dose induction chemotherapy of metastatic breast cancer in protected environment: a prospective randomized study.

To test the hypothesis of whether high doses of chemotherapy in combination achieve higher response rates and longer durations of response and survival, we treated 33 pre- and perimenopausal patients with good performance status in a prospective trial with escalating doses of fluorouracil, doxorubicin and cyclophosphamide (FAC). Patients were randomly assigned to be treated within a protected environment (laminar air flow room), with prophylactic antibiotics, or in a standard hospital room. Important patient characteristics were equally distributed in the two treatment arms. A major objective response was observed in 27 of the 32 evaluable patients (84%), and 11 (34%) achieved a complete remission (CR). There was no significant difference in overall and complete response rates between the two treatment arms, nor was there a substantial difference in times to progression or survival between the groups treated in or out of the protected environment. Comparison of the results of this study with previously reported programs of FAC chemotherapy in patients with metastatic breast cancer shows that this study achieved higher overall and complete response rates. However, neither the time to progression, nor the survival of responders or the entire patient group was different from our previous experience with standard FAC chemotherapy. When the study was initiated in 1976, the proposed dose escalation represented high-dose chemotherapy. In retrospect, even the "high" doses used in this study represent only a modest increase over standard doses of chemotherapy. Much steeper dose escalations will be needed to evaluate the efficacy of high-dose chemotherapy in breast cancer, as well as the protective value of the protected environment and prophylactic antibiotics in metastatic breast cancer.

Multivariate analysis of prognostic factors in metastatic breast cancer.

Univariate and multivariate analyses were conducted on data collected from the records of 619 patients with metastatic breast cancer in whom an Adriamycin-containing chemotherapeutic regimen was used. Using a forward, stepwise logistic regression procedure, several models or equations in which a small number of pretreatment factors were incorporated were generated and the probability of response to therapy was accurately predicted. The predictive ability of these models was tested retrospectively in 546 of the 619 patients from whom the data were derived and prospectively in a new population of 200 patients with metastatic breast cancer also treated with a therapeutically equivalent Adriamycin combination. Using similar univariate techniques, pretreatment factors were correlated with the length of survival after therapy. The proportional hazard model of Cox was used to develop a regression model relating survival to pretreatment characteristics in much the same manner as that of the response model. The total population of the initial group of patients was divided according to four levels of hazard ratio, and survival distributions were compared. This model also was tested progressively and its predictive capability was confirmed. The prediction of individual outcome is a valuable capability in the comparison of clinical trials and the continuing evaluation of biologic changes in patients with metastatic carcinoma; such a method is described in this paper.

Multimodality therapy for locally advanced and limited stage IV breast cancer: the impact of effective non-cross-resistance late-consolidation chemotherapy.

To determine the effectiveness of non-cross-resistant late-consolidation chemotherapy in locally advanced breast cancer (LABC) and stage IV breast cancer, we review our experience with two regimens. Between 1985 and 1991, we enrolled 56 patients with LABC, who were treated with a doxorubicin-based adjuvant regimen, followed by a late-consolidation non-cross-resistant regimen containing methotrexate, 5-fluorouracil, cisplatin, and cyclophosphamide. Between 1985 and 1996, a total of 45 patients with limited stage IV breast cancer underwent surgical excision of all evaluable disease, making them metastatic (stage IV) with no evaluable disease. Surgery was followed by a doxorubicin-containing regimen and then a late-consolidation non-cross-resistant regimen, which was either methotrexate, 5-fluorouracil, cisplatinum, and cyclophosphamide or 5-fluorouracil, mitomycin, etoposide, and cisplatin. Twenty-four patients with limited bone metastases that were unresectable were treated with a doxorubicin-containing regimen, radiation therapy to all sites of disease, and then one of the two late non-cross-resistant regimens. With a median follow-up of 84 months, 78% of patients with LABC are alive, and 68% are free of disease. After a median follow-up of 44 months, 53% of patients with stage IV with no evaluable disease are alive and free of disease. The use of non-cross-resistant late-consolidation chemotherapy is an effective strategy in the treatment of patients with LABC and selected patients with limited stage IV breast cancer.

Radiation-induced breast cancer.

Between 1975 and 1983, sixteen patients with a history of irradiation at an early age to the head, neck, or chest areas for a variety of conditions in whom breast cancer subsequently developed were seen at out institute. The median latent period between the irradiation and the development of breast cancer was 420 months. The distribution of patients by stage of the disease and the median age at diagnosis of this subgroup was similar to the breast cancer observed in the general population. The subsequent course of this disease was also similar to the breast cancer observed in the general population. A substantial number of women have been exposed to irradiation at a young age, and these women are at a higher risk of having breast cancer develop. These women should be closely observed to discover the disease in an early curable stage.

Diabetes insipidus and breast cancer.

Diabetes insipidus, resulting from metastatic involvement of the neurohypophysial system, is a rare complication of breast cancer. This review examined the clinical features, metastatic pattern, and radiological and postmortem findings of 39 breast cancer patients with this complication. All patients had polyuria and polydipsia, and all had evidence of advanced metastatic breast cancer. A high incidence of meningeal carcinoma carcinomatosis and/or sellar metastases was observed. In view of the anatomical proximity of the posterior pituitary to the dura mater and the sella turcica, our findings suggest that metastases to the neurohypophysis can occur not only as a result of hematogenous dissemination of malignant cells, but also from direct tumor extension and/or invasion from adjacent structures. Although satisfactory symptomatic relief can be obtained with vasopressin tannate, complete resolution of the diabetic insipidus syndrome was evident only in those patients who had achieved control of the underlying breast disease.

Thyroid-stimulating hormone and prolactin levels in breast cancer.

Serum thyroid-stimulating hormone (TSH) and prolactin (PRL) levels were measured before and after intravenous administration of protirelin to 148 patients with breast carcinoma. There was a high prevalence (36%) of elevated basal TSH; however, most of the patients were euthyroid and had normal serum thyroxine and T3 resin uptake. The PRL level was elevated in 22% of the cases. Both the mean PRL and the mean TSH levels for the breast cancer patients were significantly elevated above the respective means in a control group. We could find no correlation between serum TSH and PRL levels, suggesting that the purported association between a decreased thyroid state and breast cancer is probably not mediated through an increased PRL level. The mean survival and mean disease-free interval were shorter for patients with either elevated TSH or elevated PRL levels, but in neither case was the difference statistically significant.