Life-threatening interstitial lung disease associated with trastuzumab: case report.

A female patient with HER2 positive, metastatic breast cancer presented with pulmonary infiltrates, and a plural effusion dyspnoea after several months of trastuzumab treatment. She had been treated without complications with six courses of docetaxel and trastuzumab in combination with dexamethasone with partial remission of disease. Malignancy, infection and cardiomyopathy were excluded as causes of dyspnoea. Pleural and broncheoalveolar fluid analyses (BAL) showed eosinophils. A diagnosis of trastuzumab-induced pneumonitis was made. After treatment with steroids there was gradual clinical improvement and disappearance of infiltrates. Although a causative association between trastuzumab and this patient's pulmonary syndrome was not proven, the potential for this toxicity should be considered.

Factors influencing catheter-related infections in the Dutch multicenter study on high-dose chemotherapy followed by peripheral SCT in high-risk breast cancer patients.

Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1-141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P= <0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.

[Brain metastases in breast cancer: a special disease course for HER2 positive tumors]. / Hersenmetastasen bij het mammacarcinoom: een bijzonder beloop bij HER2-positieve tumoren.

HER2 positive breast cancers are characterized by their aggressive course of disease. Treatment with trastuzumab has significantly improved survival of patients with these cancers. Trastuzumab has few side effects, although in 10-15% of cases it is necessary to interrupt therapy because of cardiotoxicity, in most cases temporarily. It has become clear that patients receiving trastuzumab more frequently develop brain metastases than patients with a HER2 negative tumor. It is important to realize that patients with brain metastases from a HER2 positive breast tumor have a more favorable prognosis than patients with brain metastases from a HER2 negative tumor. Continuation of treatment with trastuzumab should be considered, next to the surgical intervention and/ or radiotherapy. Recently, lapatinib, a tyrosine kinase inhibitor, was registered by EMEA for patients with a HER2 positive tumor after previous treatment with anthracyclines, taxanes and trastuzumab. In combination with capacitabine, this agent leads to partial responses of cerebral metastases. More HER2 targeting drugs are expected to be introduced.

Follow-up after curative treatment for breast cancer: why do we still adhere to frequent outpatient clinic visits?

Follow-up after curative treatment for breast cancer consists of frequent outpatient clinic visits, scheduled at regular intervals. Its aim is primarily to detect local disease recurrence, or a second primary breast cancer, but also to provide information and psychosocial support. The cost-effectiveness of these frequent visits is being questioned however, leading to a search for less intensive follow-up strategies, such as follow-up by the general practitioner, patient-initiated or nurse-led follow-up or contact by telephone. These strategies are generally considered to be safe, but they are not yet widely accepted in clinical practice. Since brief interventions based on self-education and information have been shown to be able to improve quality of life, we hypothesise that these interventions may lead to a better acceptance of reduced follow-up by both patients and professionals.

Long-term update of the 24954 EORTC phase III trial on larynx preservation.

The long-term results of the EORTC 24954 trial comparing sequential versus alternating chemotherapy and radiotherapy (RT) for patients with locally advanced laryngeal and hypopharyngeal cancer are reported. From 1996 to 2004, 450 patients were randomly assigned (1-1) to a sequential arm (SA = induction cisplatin-5fluorouracil followed by a 70Gy-RT for the responders or a total laryngectomy and post-operative RT for the non-responders) and an alternating arm (AA = cisplatin-5fluorouracil alternated with three 2-week courses of 20 Gy-RT for a total dose of 60 Gy). Median follow-up was 10.2 years. Ten-year survival with functional larynx (primary end-point) and overall survival were similar in both arms (18.7% and 33.6% in SA versus 18.3% and 31.6% in AA). Late toxicity was also similar; however, a trend for higher larynx preservation and better laryngeal function was observed in AA.

Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer.

PURPOSE: A potential application of hematopoietic growth factors is to obtain an increased dose-intensity. This can be achieved by either higher doses of chemotherapy with standard intervals, or by standard doses with shorter intervals. The potential of these approaches has not been investigated systematically. PATIENTS AND METHODS: In a randomized, multicenter study, 49 advanced breast cancer patients were treated with granulocyte colony-stimulating factor (G-CSF) and either increasing doses of epirubicin and cyclophosphamide with fixed intervals (arm one) or progressively shorter intervals with fixed doses of epirubicin and cyclophosphamide (arm two). A cohort of at least six patients was studied at each interval/dose. A more intensified interval/dose was given if less than 50% of patients encountered a dose-intensity limiting criterium (DILC) in the first three courses. RESULTS: In arm one, epirubicin 140 mg/m2 and cyclophosphamide 800 mg/m2 every 21 days was too toxic. Subsequently, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 was tested with two of 10 patients encountering a DILC. All initial DILCs consisted of febrile neutropenia. In arm two, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely with 14- and 12-day intervals. In the 10-day interval, eight of 12 patients completed the first three cycles without a DILC. In the 8-day interval, seven of eight patients encountered a DILC. Incomplete neutrophil recovery, and to a lesser extent stomatitis, were dose-limiting. CONCLUSION: In combination with G-CSF, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 every 21 days was feasible (projected dose-intensity, 40 mg/m2/wk and 233 mg/m2/wk, respectively). Epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely every 10 days, allowing a projected dose-intensity of 52.5 mg/m2/wk and 350 mg/m2/wk, respectively.

Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group.

PURPOSE: This phase III study compared docetaxel with mitomycin plus vinblastine (MV) in patients with metastatic breast cancer (MBC) progressing despite previous anthracycline-containing chemotherapy. PATIENTS AND METHODS: Patients (n=392) were randomized to receive either docetaxel 100 mg/m2 intravenously (i.v.) every 3 weeks (n=203) or mitomycin 12 mg/m2 i.v. every 6 weeks plus vinblastine 6 mg/m2 i.v. every 3 weeks (n=189), for a maximum of 10 3-week cycles. RESULTS: In an intention-to-treat analysis, docetaxel produced significantly higher response rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to previous anthracycline agents (30% v 7%). Median time to progression (TTP) and overall survival were significantly longer with docetaxel than MV (19 v 1 weeks, P=.001, and 1 1.4 v 8.7 months, P=.0097, respectively). Neutropenia grade 3/4 was more frequent with docetaxel (93.1 % v62.5%; P < .05); thrombocytopenia grade 3/4 was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic nonhematologic adverse events were infrequent in both groups. Withdrawal rates because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%; docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was limited by a number of factors, but results were similar in both groups. CONCLUSION: Docetaxel is significantly superior to MV in terms of response, TTP, and survival. The safety profiles of both therapies are manageable and tolerable. Docetaxel represents a clear treatment option for patients with MBC progressing despite previous anthracycline-containing chemotherapy.

An unusual cause of diplopia in a cancer patient.

A 47-year-old woman with metastatic infiltrating lobular carcinoma of the breast developed diplopia. Computed tomography of the orbits showed enlargement and irregularity of the right inferior rectus and inferior obliques muscles. Biopsies of these muscles contained breast carcinoma cells. This case report discusses the causes of diplopia in cancer patients, with special attention to the diagnostic problems of metastasis in extraocular muscles. The possible combined occurrence of metastasis in the leptomeninges and extraocular muscles is also to be borne in mind if the latter diagnosis is not to be missed.

Loco-regional recurrences after mastectomy in breast cancer: prognostic factors and implications for postoperative irradiation.

PURPOSE: Potential risk factors including DNA flow cytometric-derived parameters predicting loco-regional recurrence (LRR) in early breast cancer were investigated. MATERIALS AND METHODS: This study included 608 patients treated by modified radical mastectomy between 1982 and 1987. Recommendations regarding local treatment as well as adjuvant systemic therapy did not change during this period. Patients treated by adjuvant chemotherapy were randomized to receive additional medroxyprogesterone acetate (MPA) treatment. Only 59 (10%) patients received postoperative irradiation (XRT) to the chest wall and/or axillary lymph nodes; another 121 (20%) patients received XRT to the internal mammary nodes because of centromedially located tumours. RESULTS: Patients were followed for a median period of 7.5 years. The event-free survival at 10 years was 50%. The cumulative incidence rate of LRR at 10 years was 18% (n = 93), either with (n = 30) or without (n = 63) concurrent distant metastases. The chest wall, regional lymph nodes or both were involved in 41 (44%), 38 (41%) and 12 (13%) patients, respectively. Multivariate analysis according to the Cox model revealed two factors associated with LRR, i.e. pT (P < 0.05) and nodal status (P < 0.05). In node-positive patients extracapsular tumour extension (ECE) and pT were independent risk factors. DNA ploidy and S-phase fraction did not yield additional information. Based on pT, nodal status and extracapsular extension of tumour growth a high risk (> 10%) and low risk (< 10%) group for LRR could be identified. CONCLUSIONS: Results indicate that T-stage and nodal status, combined with ECE, may help to identify patients at risk for loco-regional recurrence, whereas DNA flow cytometry does not.

High-dose chemotherapy with autologous bone marrow support as consolidation after standard-dose adjuvant therapy in primary breast cancer patients with seven or more involved axillary lymph nodes.

Despite adjuvant chemotherapy the prognosis of patients with breast cancer and a high number of involved axillary lymph nodes is very poor. The aim of the present study was to evaluate the efficacy of high-dose chemotherapy with autologous bone marrow support in patients with seven or more involved axillary lymph nodes. Nineteen patients underwent four courses of standard adjuvant chemotherapy, followed by high-dose busulphan/cyclophosphamide chemotherapy with autologous bone marrow support. The median age was 41.4 years and the median number of involved lymph nodes 11. Mucositis WHO grade > or = 3 was observed in 15 patients and 18 patients suffered febrile neutropenia. Transplant-related mortality was encountered in two patients, due to hepatic veno-occlusive disease and sepsis complicated by multi-organ failure, respectively. After a median follow-up period of 1490 days (range 582-2024 days) from diagnosis, nine patients have relapsed and the overall event-free survival (EFS) is 42% (95% CI 19-65%). The median EFS is 487 days. High-dose treatment with BuCy2 in high-risk breast cancer patients is a toxic regimen and does not seem to improve disease-free survival.

Adjuvant chemo-hormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate (MPA) for node-positive cancer patients, update at 12 years follow up.

An update with 10 years of follow up of a study adding adjuvant MPA to CAF chemotherapy is presented. A total of 409 patients were entered, of which 200 were randomized to receive 500 mg of MPA i.m. on days 1-28 and twice per week thereafter for 6 months. There was a significant improvement in metastases-free and overall survival in women >60 years of age receiving MPA (P=0.01 and P=0.02 respectively). A detrimental effect of MPA was seen in women <40 years. Possible reasons for these results are discussed.

Relevance of the expression of bcl-2 in combination with p53 as a prognostic factor in breast cancer.

BACKGROUND: Both the proto-oncogene bcl-2 and the tumour suppressor gene p53 are involved in the regulation of apoptosis. PATIENTS AND METHODS: We have investigated the prognostic value of the immunohistochemical expression of p53 and bcl-2 separately and in combination in a group of 345 breast cancer patients from one hospital with a long median follow-up of more than 10 years. RESULTS: Bcl-2 expression was not a prognostic factor. p53 was an independent prognostic factor for overall survival (p = 0.005) and for post-relapse survival (p = 0.006). Looking at bcl-2/p53 subgroups in the bcl-2 positive subgroup there was a large difference in both disease-free and overall survival between p53 negative and p53 positive patients. In the bcl-2 negative subgroup the p53 status was not a prognostic factor at all. CONCLUSIONS: p53 is an independent prognostic factor for overall survival and post-relapse survival. However, p53 status is only important in the bcl-2 positive subgroup.

pS2 is an independent prognostic factor for post-relapse survival in primary breast cancer.

BACKGROUND: The pS2 protein is involved in the maintenance of the integrity of the gastrointestinal tract. In breast cancer pS2 can be demonstrated in at least half of the tumors and probably reflects the functional status of ER. Several features make it likely that pS2 is involved in growth regulation. PATIENTS AND METHODS: We have investigated the value of immunohistochemical pS2 determination as a prognostic factor in 339 breast cancer patients with long follow-up from one hospital. RESULTS: A prognostic role for pS2 could not be demonstrated considering disease-free and overall survival, although in pS2-negative tumors a trend for less locoregional relapse was found. However, in multivariate analysis pS2 showed independent prognostic value for post-relapse survival. CONCLUSIONS: PS2 is an independent prognostic factor for post-relapse survival, most likely because it is a predictive factor for response to systemic therapy.

The prognostic significance of steroid receptor activity in tumor tissues of patients with primary breast cancer.

The prognostic significance of steroid-receptor activity is still debatable. Discrepancies in results are probably attributable to few patients, heterogeneous patient populations, and short follow-up. We investigated the prognostic significance of estrogen- and progesterone-receptor (ER and PgR, respectively) activity as a continuous variable in a homogeneous patient population. The prognostic significance of steroid-receptor activity was examined in 329 node-negative and 320 node-positive unselected breast cancer patients. In node-negative patients, ER values of primary tumors between 100 and 400 fmol/mg protein appeared to be a significant predictor for low risk of recurrence, whereas high ER (> 400) revealed an unfavorable prognosis. The classic cutoff level of ER (< 10 fmol/mg proteins) had no prognostic significance, however. In patients receiving adjuvant chemotherapy--the node-positive breast cancer patients--the classic cutoff value of ER (10 fmol/mg protein) predicts significantly distant metastases-free survival and overall survival only in the first 4 years of follow-up after diagnosis. Progesterone receptor is a time-dependent prognosticator in node-negative breast cancer patients (cutoff point for PgR, 80 fmol/mg). In node-positive breast cancer patients treated with chemotherapy or a combination of chemo- and hormonal therapy, PgR values lower than 60 fmol/mg had a worse prognosis. The results show the poor performance of standard cutoff points for ER and PgR positivity in predicting prognosis. Better prognosis is related to higher receptor levels but this relation is predominantly time-dependent. Moreover, patients who have high ER levels have a prognosis that is worse when compared with intermediate ER levels. Standard cutoff points for steroid receptors should not be used to select patients for prognosis.

Mammography in the follow-up after breast-conserving treatment in cancer of the breast: suitability for mammographic interpretation, validity and interobserver variation.

The aims of this study were to determine the suitability for radiographic interpretation, interobserver variability and validity of mammography after breast-conserving treatment. Initial and post-treatment mammograms of 100 consecutive patients treated between 1982 and 1987, with a minimal follow-up of 5 years, were independently selected for review by two radiologists. Mammograms were classified according to suitability for interpretation and radiological diagnosis based on the presence of characteristics of malignancy. The interobserver variability was expressed in kappa values, the validity in a receiver operating characteristic (ROC) plot. 534 post-treatment and 86 initial mammograms of 92 patients were obtained. Suitability for interpretation was not different from pre-treatment mammograms and was significantly associated with age, being better in the age group over 50 years. No association was observed between suitability for interpretation and treatment-related factors, even if irradiation was combined with concurrent chemotherapy. Reliability of conclusions regarding sensitivity and specificity in this study are limited due to the small number of events. Interobserver agreement concerning classification was moderate (weighted kappa = 0.49). ROC analysis showed an optimal decision threshold between the "uncertain" and "suspect" categories of malignancy, resulting in a sensitivity of 86% and a specificity of 98%. The appearance of new pathological microcalcifications with or without tumour mass seemed to be the most important characteristics of malignancy predicting local relapse. No clear alteration in suitability for interpretation was observed in the mammograms after breast-conserving treatment, even if irradiation was combined with concurrent chemotherapy. Mammography after breast conserving-treatment may be slightly less sensitive but is equally specific compared with mammography in the screening situation.

[Breast cancer in patients, 70 years or older]. / Borstkanker bij patiënten van 70 jaar en ouder.

Over 30% of breast cancers are diagnosed after age 70. The incidence of breast cancer in the elderly has increased since 1960. Risk factors for breast cancer are a medical history without pregnancy, a first pregnancy after age 30 and the use of hormonal replacement therapy. The biology of breast cancer at advanced age indicates a relative slow, less aggressive and hormone dependent tumour growth. In spite of these favourable characteristics, the prognosis is not better than at middle age. Over 20% of older patients die from co-existing other diseases within 5 years after the diagnosis of breast cancer. This comorbidity, mostly cardiovascular or pulmonary, affects the possibilities and the outcome of treatment. Treatment of the primary tumour is performed according to the same guidelines as in younger patients. Indication exists for hormonal adjuvant treatment with tamoxifen in patients with oestrogen receptor positive tumours. Hormonal treatment is the treatment of choice in metastatic disease. Chemotherapy is given in patients with oestrogen receptor negative tumours and in patients with progressive hepatic or pulmonary metastases.

[Adjuvant systemic therapy for patients with resectable breast cancer: guideline from the Dutch National Breast Cancer Platform and the Dutch Society for Medical Oncology]. / Adjuvante systemische therapie voor patiënten met resectabel mammacarcinoom; richtlijn van het Nationaal Borstkanker Overleg Nederland en de Nederlandse Vereniging voor Medische Oncologie.

There is an abundance of evidence that adjuvant systemic therapy with chemotherapy or endocrine therapy results in better survival for all patients with resectable breast cancer. The absolute 10-year survival advantage however varies for the different patient groups. Therefore, for each individual patient the choice of adjuvant therapy must take into account the potential benefits and the possible side effects. A group of medical oncologists from the Dutch National Breast Cancer Platform (NABON) and the Dutch Society for Medical Oncology (NVMO) prepared a guideline for the treatment of patients with early resectable breast cancer. The criterium for choosing adjuvant systemic therapy for the individual patient is an expected increase in 10-year survival of 5% or more. In the guideline a difference is made between patients with and without axillary lymph node metastasis. In patients with axillary lymph node metastasis the choice for adjuvant systemic therapy depends on the following prognostic factors: menopausal status, age, and the presence of estrogen and progesterone receptors in the tumour. In patients without axillary lymph node metastasis the choice depends also on the following prognostic factors: the size of the tumour, the mitotic activity index, or the histopathologic grade of differentiation.

Nurse-led telephone follow-up and an educational group programme after breast cancer treatment: results of a 2 × 2 randomised controlled trial.

OBJECTIVE: To investigate whether frequent hospital follow-up in the first year after breast cancer treatment might partly be replaced by nurse-led telephone follow-up without deteriorating health-related quality of life (HRQoL), and whether a short educational group programme (EGP) would enhance HRQoL. PATIENTS AND METHODS: A multicentre pragmatic randomised controlled trial (RCT) with a 2×2 factorial design was performed among 320 breast cancer patients who were treated with curative intent. Participants were randomised to follow-up care as usual (3-monthly outpatient clinic visits), nurse-led telephone follow-up, or the former strategies combined with an educational group programme. The primary outcome for both interventions was HRQoL, measured by EORTC QLQ-C30. Secondary outcomes were role and emotional functioning and feelings of control and anxiety. RESULTS: Data of 299 patients were available for evaluation. There was no significant difference in HRQoL between nurse-led telephone and hospital follow-up at 12 months after treatment (p = 0.42; 95% confidence interval (CI) for difference: -1.93-4.64) and neither between follow-up with or without EGP (p = 0.86; 95% CI for difference: -3.59-3.00). Furthermore, no differences between the intervention groups and their corresponding control groups were found in role and emotional functioning, and feelings of control and anxiety (all p-values > 0.05). CONCLUSION: Replacement of most hospital follow-up visits in the first year after breast cancer treatment by nurse-led telephone follow-up does not impede patient outcomes. Hence, nurse-led telephone follow-up seems an appropriate way to reduce clinic visits and represents an accepted alternative strategy. An EGP does not unequivocally affect positive HRQoL outcomes.

Economic evaluation of four follow-up strategies after curative treatment for breast cancer: results of an RCT.

BACKGROUND: An economic evaluation was performed alongside a randomised controlled trial (ISRCTN 74071417) investigating the cost-effectiveness of nurse-led telephone follow-up instead of hospital visits, and of a short educational group programme (EGP) in the first year after breast cancer treatment. METHOD: This economic evaluation (n = 299) compared the one-year costs and the effects of four follow-up strategies: (1) hospital follow-up; (2) nurse-led telephone follow-up; (3) hospital follow-up plus EGP; and (4) nurse-led telephone follow-up plus EGP. Costs were measured using cost diaries and hospital registrations. Quality-adjusted life years (QALYs) were measured using the EQ-5D. Outcomes were expressed in incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves. RESULTS: Hospital follow-up plus EGP yielded most QALYs (0.776), but also incurred the highest mean annual costs (€4914). The ICER of this strategy versus the next best alternative, nurse-led telephone follow-up plus EGP (0.772 QALYs and €3971), amounted to €235.750/QALY. Hospital and telephone follow-up without EGP both incurred higher costs and less QALYs than telephone follow-up plus EGP and were judged inferior. Hospital follow-up plus EGP was not considered cost-effective, therefore, telephone follow-up plus EGP was the preferred strategy. The probability of telephone follow-up plus EGP being cost-effective ranged from 49% to 62% for different QALY threshold values. Secondary and sensitivity analyses showed that results were robust. CONCLUSION: Nurse-led telephone follow-up plus EGP seems an appropriate and cost-effective alternative to hospital follow-up for breast cancer patients during their first year after treatment.