The use of breast imaging for predicting response to neoadjuvant lapatinib, trastuzumab and their combination in HER2-positive breast cancer: Results from Neo-ALTTO.

AIM: To determine the value of mammography and breast ultrasound (US) in predicting outcomes in HER2 positive breast cancer patients (pts) within Neo-ALTTO trial. PATIENTS AND METHODS: Mammography and US were required at baseline, week 6 and surgery. Two independent blinded investigators reviewed the measurements and assigned the corresponding response category. Pts showing complete or partial response according to RECIST (v1.1) were classified as responders. The association between imaging response at week 6 or prior to surgery was evaluated with respect to pathological complete response (pCR) and event-free Survival (EFS). RESULTS: Of the 455 pts enrolled in the trial, 267 (61%) and 340 (77%) had evaluable mammography and US at week 6; 248 (56%) and 309 (70%) pts had evaluable mammography and US prior to surgery. At week 6, 32% and 43% of pts were classified as responders by mammography and US, respectively. pCR rates were twice as high for responders than non-responders (week 6: 46% versus 23% by US, p < 0.0001; 41% versus 24% by mammography, p = 0.007). Positive and negative predictive values of mammography and US prior to surgery were 37% and 35%, and 82% and 70%, respectively. No significant correlation was found between response by mammography and/or US at week 6/surgery and EFS. CONCLUSIONS: Mammography and US were underused in Neo-ALTTO although US had the potential to assess early response whereas mammography to detect residual disease prior to surgery. Our data still emphasise the need for further imaging studies on pts treated with neoadjuvant HER2-targeted therapy.

First-line bevacizumab-containing therapy for breast cancer: results in patients aged≥70 years treated in the ATHENA study.

BACKGROUND: There are limited data on treatment outcomes in the growing population of elderly patients with locally recurrent/metastatic breast cancer (LR/mBC). To gain information on first-line bevacizumab combined with chemotherapy in the elderly, we analyzed data from the ATHENA trial in routine oncology practice. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor-2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We carried out a subgroup analysis of safety and efficacy in patients aged≥70 years. Possible correlations between tolerability and baseline comorbidities or Eastern Cooperative Oncology Group status were explored. RESULTS: Bevacizumab was combined with single-agent paclitaxel in 46% of older patients. Only hypertension and proteinuria were more common in older than in younger patients (grade≥3 hypertension: 6.9% versus 4.2%, respectively; grade≥3 proteinuria: 4.0% versus 1.5%, respectively). Grade≥3 arterial/venous thromboembolism occurred in 2.9% versus 3.3%, respectively. Further analysis revealed no relationship between baseline presence and severity of hypertension and risk of developing hypertension during bevacizumab-containing therapy. Median time to progression was 10.4 months in patients aged≥70 years. CONCLUSIONS: These findings suggest that bevacizumab-containing therapy is tolerable and active in patients aged≥70 years. Hypertension was more common than in younger patients but was manageable. We find no evidence precluding the use of bevacizumab in older patients, including those with hypertension, although age may influence chemotherapy choice.

What is the role of chemotherapy in estrogen receptor-positive, advanced breast cancer?

Most breast tumors depend on female sex hormones for development and growth, thus being amenable to endocrine therapies. In the management of estrogen receptor (ER)-positive, advanced breast cancer, conventional wisdom dictates the use of endocrine therapy for patients with good prognostic features, whereas chemotherapy is recommended for the treatment of visceral crisis. There is, however, considerable uncertainty regarding the best initial strategy for patients with poor prognostic features other than visceral crisis, such as small-volume visceral involvement and a short disease-free interval after adjuvant therapy. In this article, we examine the role of chemotherapy in ER-positive, advanced breast cancer. Our review of the literature suggests that, in the absence of visceral crisis, endocrine agents should always be considered a major option for the initial treatment of ER-positive, metastatic breast cancer due to their proven efficacy and favorable toxicity profile. Although certain chemotherapy agents can induce higher response rates and more rapid responses, which are desirable effects in particular situations, the up-front use of chemotherapy does not seem to influence the overall outcome of the disease. In the subset of patients with epidermal growth factor type 2-positive disease, on the other hand, current data still do not support the use of endocrine agents alone.

Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study.

BACKGROUND: A randomized, double-blind, multicenter study was conducted to compare the anti-tumor activity of letrozole vs. tamoxifen in postmenopausal women with ER and/or PgR positive primary untreated breast cancer. PATIENTS AND METHODS: Three hundred thirty-seven postmenopausal women with ER and/or PgR positive primary untreated breast cancer were randomly assigned once daily treatment with either letrozole 2.5 mg or tamoxifen 20 mg for four months. At baseline none of the patients were considered to be candidates for breast-conserving surgery (BCS) and 14% of the patients were considered inoperable. The primary endpoint was to compare overall objective response (CR + PR) determined by clinical palpation. Secondary endpoints included overall objective response on ultrasound and mammography and the number of patients who qualified for BCS. RESULTS: Overall objective response rate (clinical palpation) was statistically significantly superior in the letrozole group, 55% compared to tamoxifen, 36% (P < 0.001). Secondary endpoints of ultrasound response, 35% vs. 25% (P = 0.042), mammographic response, 34% vs. 16% (P < 0.001), and BCS, 45% vs. 35% (P = 0.022) between the letrozole and tamoxifen groups, respectively, showed letrozole to be significantly superior. Both treatments were well tolerated. CONCLUSIONS: This study shows that letrozole is more effective than tamoxifen as preoperative therapy in postmenopausal patients with ER and/or PgR positive primary untreated breast cancer and is at least as well tolerated.

Assessment of bone response to systemic therapy in an EORTC trial: preliminary experience with the use of collagen cross-link excretion. European Organization for Research and Treatment of Cancer.

This study was designed to evaluate new bone resorption and tumour markers as possible alternatives to serial plain radiographs for the assessment of response to treatment. Thirty-seven patients with newly diagnosed bone metastases from breast cancer, randomized to receive oral pamidronate or placebo tablets in addition to anticancer treatment within the context of a multicentre EORTC trial, who were both assessable for radiographic response in bone and had serum and urine samples collected for more than 1 month were studied. The markers of bone metabolism measured included urinary calcium (uCa), hydroxyproline (hyp), the N-telopeptide cross-links of type I collagen (NTx) and total alkaline phosphatase. The tumour markers measured were CA15-3 and cancer-associated serum antigen (CASA). Before treatment, levels of Ntx, uCa and Hyp were elevated in 41%, 24% and 28% respectively, and CA15-3 and CASA increased in 69% and 50%. For assessment of response and identification of progression, Ntx was the most useful bone marker. All markers behaved similarly in no change (NC) and partial response (PR) patients. There was a significant difference (P < or = 0.05) in Ntx levels (compared to baseline) at 1 and 4 months and in CA15-3/CASA at 4 months between patients with PR or NC and those with progressive disease (PD), and at 4 months between those with time to progression (TP) > 7 and those with TP < or = 7 months. The diagnostic efficiency (DE) for prediction of PD following a > 50% increase in Ntx or CA15-3 was 78% and 62% respectively. An algorithm to predict response to therapy has been developed for future prospective evaluation.

Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease.

BACKGROUND: Bisphosphonates are an important component of the treatment of metastatic bone disease but more potent, oral formulations are required to improve the effectiveness and convenience of treatment. An oral formulation of the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed. PATIENTS AND METHODS: One hundred ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this double blind placebo-controlled evaluation of four oral dose levels (5, 10, 20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. After an initial four-week tolerability phase, patients could continue on treatment for a further three months without unblinding; patients initially allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary calcium excretion (UCCR). Bone resorption was also assessed by measurement of pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules. RESULTS: Two patients did not receive any trial medication thus, 108 patients were evaluable for safety. Ninety-two patients were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39%, 80% and 74% respectively. One or more gastrointestinal (GI) adverse events occurring in the first month of treatment were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%) patients at the placebo, 5, 10, 20 and 50 mg dose levels respectively. One patient (20 mg dose) developed radiographically confirmed oesophageal ulceration. GI tolerability may have been adversely affected by concomitant administration of non-steroidal anti-inflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI intolerability but these patients were evenly distributed across the five treatment groups. There was no difference in non-GI adverse events between groups. CONCLUSIONS: Oral ibandronate has potent effects on the rate of bone resorption at doses which are generally well tolerated. Further development is appropriate to evaluate the effects of long-term administration in the prevention of metastatic bone disease and the management of established skeletal metastases.

Vorozole (Rivizor): an active and well tolerated new aromatase inhibitor for the treatment of advanced breast cancer patients with prior tamoxifen exposure. Investigational Drug Branch of the European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Cooperative Group.

Vorozole (Rivizor) is a potent and stereospecific inhibitor of aromatase having shown promising endocrine effects in phase I studies. In the present trial, 27 postmenopausal patients with advanced breast cancer, measurable lesions, presumably hormone responsive (ER or PR+, or ER? with disease-free survival longer than 1 year, or prior documented response to tamoxifen), were treated with vorozole one tablet 2.5 mg daily. All had been previously treated with tamoxifen as adjuvant (two patients) or for advanced disease (24 patients), or both (one patient). Objective remissions were observed in eight patients (30%) with two complete responses (CR) and six partial responses (PR) lasting for a median of 14.3 months (range 6.8-40.6); nine stabilizations were also recorded (median 7.9 months; range 3.7-40.1). Median time to progression for the 27 patients was 5.9 months. Sites of response were skin (three patients), lymph nodes (two patients), lung (two patients) and chest wall plus lymph nodes (one patient). Treatment was very well tolerated: mild hot flushes (four patients), gastrointestinal complaints (four patients) and no significant toxicity (common toxicity criteria grade above 2) or drug-related severe adverse event. It is concluded that vorozole is an active second-line endocrine treatment, deserving consideration for randomized comparison with other agents such as aminoglutethimide, megestrol acetate or medroxyprogesterone acetate.

High dose pamidronate: clinical and biochemical effects in metastatic bone disease.

Eighty-six patients with heavily pretreated progressive bone metastases (52 with breast carcinoma, 17 with prostate carcinoma, and 17 others) were included in 2 studies designed to assess the clinical and biochemical effects of a single 120 mg, 2-hour infusion of pamidronate. No other systemic anticancer treatment or radiotherapy were administered. Pamidronate had a significant beneficial effect, with a reduction in a symptom score measuring pain, World Health Organization performance status, and analgesic consumption and improvement in quality of life when compared with a placebo infusion. Symptomatic improvement corresponded with changes in the rate of bone resorption as indicated by the concentrations of pyridinoline crosslinks in the urine. In patients with the highest rates of bone resorption (N-terminal peptide-bound portion of the collagen crosslink or crosslaps excretion > or = twice that of normal) clinical response or normalization of the rate of bone resorption were rarely observed, with all clinical responses occuring in those patients with bone resorption rates of < twice that of normal. Intriguingly, symptomatic response also correlated with a modest (> 10%) fall in tumor marker levels, suggesting a possible effect of bisphosphonates on tumor activity.

Evaluation of new bone resorption markers in a randomized comparison of pamidronate or clodronate for hypercalcemia of malignancy.

PURPOSE: To compare the effects of two bisphosphonates on markers of bone resorption in a randomized double-blind trial for the treatment of hypercalcemia of malignancy. PATIENTS AND METHODS: Thirty-two patients with a serum calcium (sCa) level > or = 2.7 mmol/L that persisted after 48 hours of saline rehydration were randomized to receive pamidronate 90 mg or clodronate 1,500 mg. Bone resorption markers measured included urinary calcium (uCa), hydroxyproline (Hyp), deoxypyridinoline (Dpd), pyridinoline (Pyd), the cross-linking molecule at either the N-telopeptide (NTx) or the C-telopeptide (Crosslaps) regions of type I collagen, and free Dpd. RESULTS: Both bisphosphonates restored normocalcemia, but the duration of action was longer after pamidronate (P < .01). There was a mean pretreatment sevenfold increase in NTx, fivefold increase in Dpd and Crosslaps, and 2.5-fold increase in free Dpd. The changes in uCa were confounded by an increase in parathyroid hormone (PTH) (P < .05), which, through effects on the kidney, inhibits calcium excretion. Most resorption markers showed a larger decrease after pamidronate than clodronate (P < .01). NTx and Crosslaps showed the greatest decrease, being significantly different from any other marker in both arms (P < .01). There was a significant correlation between Dpd, NTx, and Crosslaps (P < .002), but not with uCa. CONCLUSION: The superiority of pamidronate in controlling hypercalcemia is mirrored by the changes observed in these markers. uCa is not an accurate bone resorption marker, which reflects the renal handling of calcium by PTH. NTx and Crosslaps showed the largest increase at baseline and the greatest change after treatment, which suggests these new markers may be more sensitive indicators of bone resorption.

Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease.

PURPOSE: The aim of this study was to evaluate pamidronate for bone pain in a randomised double-blind trial and to evaluate the contribution of new markers of bone resorption in patients with bone metastases. PATIENTS AND METHODS: Fifty-two patients with painful bone metastases were randomised to receive a two-hour infusion of pamidronate 120 mg or an identical infusion of saline. Four weeks later, all patients received pamidronate 120 mg. Bone resorption markers measured included urinary calcium (uCa), hydroxyproline (Hyp), and the collagen breakdown products: NTx, Crosslaps and Free Dpd. RESULTS: Symptomatic response during the first four weeks was seen after pamidronate, but not with placebo (P < 0.05). Quality of life was maintained with pamidronate and deteriorated after placebo (P < 0.05). Resorption markers did not decrease after placebo, but NTx and Crosslaps both decreased by 70% after pamidronate (P = 0.001). A second infusion of pamidronate did not decrease resorption further, but maintained the suppression of resorption at similar levels for a further four weeks. Symptomatic response to pamidronate correlated closely with the rate of bone resorption; it was more frequent in those patients with an initial NTx value of < 2 times the upper limit of normal (17 of 27, 62%) and in those where the level of Ntx returned to normal (19 of 32, 59%), than in the patients with either high baseline values of NTx (> 2 times the upper limit of normal) or Ntx levels which failed to normalise for whom the response frequencies were 2 of 16 (13%) and 0 of 11 (0%), respectively. CONCLUSIONS: Subjective benefit after intravenous pamidronate is confirmed in this placebo-controlled study. The new bone resorption markers of collagen breakdown were able to predict clinical response to pamidronate.

Metabolic effects of pamidronate in patients with metastatic bone disease.

We have evaluated the value of specific bone resorption markers in monitoring metastatic bone disease to define the duration of action of a single high-dose pamidronate infusion. Twenty patients received a single infusion of pamidronate 120 mg for painful bone metastases. Ten out of these 20 patients also received a second infusion. They were evaluated at baseline, 2, 4 and 8 weeks after each infusion. A composite pain questionnaire, serum and urine tests were carried out at these time points. Bone resorption markers measured included urinary calcium, hydroxyproline and two new markers: pyridinoline and deoxypyridinoline. Reference values were defined by 20 healthy controls matched by age and sex. Pamidronate induced a profound fall in bone resorption with a maximal effect within the first month after therapy. Changes in urinary calcium levels were confounded by a rise of 100% in the parathyroid hormone levels. Before treatment, pyridinoline and deoxypyridinoline were increased in 70% of patients, while urinary calcium was increased in only 40% of them. Thirteen patients had a > or = 50% fall in deoxypyridinoline levels and were considered as biochemical responders. These patients had a mean reduction in pain score of about 30% of baseline levels, which was significantly higher than the seven non-biochemical responders. In conclusion, urinary calcium is not a precise marker of bone resorption. Deoxypyridinoline seems to be the most specific bone resorption marker in cancer patients. Biochemical responders have the most benefit from pamidronate in terms of pain relief. This suggests that patients may benefit from more potent or repeated infusions of bisphosphonates.

The future of bisphosphonates in cancer.

Bisphosphonates, in conjunction with rehydration, are now the treatment of choice for hypercalcaemia of malignancy. They can also relieve bone pain and improve quality of life as single agent therapy and, in conjunction with systemic anticancer treatments, can prevent skeletal complications and slow down the metastatic process. The clinical effects are greatest and most clearly defined in breast cancer and multiple myeloma, but, theoretically, clinical benefit should be achievable across the entire spectrum of metastatic bone disease. The new biochemical markers for measuring bone resorption are for the first time providing a direct assessment of the effects of treatment on bone. It is hoped that they will enable a more scientific selection of the type, dose and schedule of bisphosphonate required for the best compromise between efficacy, convenience and patient acceptability. We can expect to see a rapid increase in the use of bisphosphonates in malignancy (especially breast cancer and myeloma). Careful assessment of the health-care economics of this new treatment modality is urgently needed.

Phase II study of teniposide in patients with AIDS-related Kaposi's sarcoma.

Antitumour activity of cytotoxic agents, evaluated in patients with AIDS-related Kaposi's sarcoma (KS), is about 30-80%. However, responses are mostly partial and short. Experience with etoposide is similar. Teniposide has a longer elimination half-life and superior antitumour activity compared with etoposide in some experimental models. Thus a phase II trial was done in 25 patients with AIDS-related KS. Teniposide was given by 60-min infusion at 360 mg/m2 every 3 weeks. 10 (40%) showed a partial response, median duration of 9 (6-20) weeks. The main side-effects were leukopenia, thrombocytopenia, nausea and vomiting, alopecia and mucositis.