Wil V. Dolsma

Prospective Evaluation of Early Cardiac Damage Induced by Epirubicin-Containing Adjuvant Chemotherapy and Locoregional Radiotherapy in Breast Cancer Patients

PURPOSE To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients. PATIENTS AND METHODS Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction. RESULTS No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P =.001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P <.01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P =.04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P <.01). No persistent alterations were found in diastolic function and HRV. CONCLUSION Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.

Three-dimensional conformal hypofractionated simultaneous integrated boost in breast conserving therapy: Results on local control and survival

PURPOSE To report on local control and survival after breast conserving therapy (BCT) including three-dimensional conformal simultaneous integrated boost irradiation (3D-CRT-SIB) and on the influence of age on outcome. PATIENT AND METHODS For this study, 752 consecutive female breast cancer patients (stages I-III), treated with 3D-CRT-SIB at the University Medical Center Groningen from 2005 to 2008, were retrospectively identified. Median age was 58.4 (range 26-84) years. The SIB fractionation used was: 28×1.8Gy (whole breast) and 28×2.3Gy or 2.4Gy (tumour bed). Next to outcome, we estimated the effect of age on the recurrence-free period (RFP) by multivariate Cox regression survival analysis. RESULTS Median follow-up was 41 (range 3-65) months. Local control was 99.6% at 3 years (6 ipsilateral recurrences). The 3-year locoregional control, RFP and overall survival (OS) rates were 99.2%, 95.5%, and 97.1%, respectively. In multivariate analysis, tumours >2cm (hazard ratio (HR) 3.11; 95% confidence interval (CI) 1.57-6.17) and triple negativity (HR 3.03; 95% CI 1.37-6.67) and not age were associated with impaired RFP. CONCLUSIONS At 3 years, the 3D-CRT-SIB technique in BCT results in excellent local control and OS. Age was not a risk factor for any recurrence.

Intensive chemotherapy with autologous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes

Patients with breast cancer and a high number of involved axillary lymph nodes have a poor prognosis, despite adjuvant chemotherapy. The 5-year disease-free survival (DFS) in this group amounts to 30-40% and the 10-year DFS is only 15-20%. Therefore, new treatment modalities are being sought for this group of patients. The aim of the present study was the evaluation of the efficacy of high-dose chemotherapy combined with autologous bone marrow support. 24 patients with a primary breast cancer with more than five involved axillary lymph nodes received, after surgery, six courses of induction chemotherapy followed by ablative chemotherapy and reinfusion of autologous bone marrow. All patients were premenopausal or less than 2 years postmenopausal. Induction chemotherapy consisted of methotrexate (MTX) 1.5 g/m2 intravenous (i.v.) and 5-fluorouracil (5-FU) 1.5 g/m2 i.v. on day 1, prednisone 40 mg/m2 orally on days 2-14, doxorubicin 50 mg/m2 i.v. and vincristine 1 mg/m2 i.v. on day 14. Courses were repeated six times every 4 weeks. 10 patients received cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. as intensive regimen, in 14 patients this comprised mitoxantrone 50 mg/m2 i.v. and thiotepa 800 mg/m2 i.v. Reinfusion of autologous marrow followed on day 7. Finally, patients received locoregional radiotherapy for extranodal disease and tamoxifen 40 mg daily orally over a period of 2 years. The median age of patients was 42 years, range 29-54. The median number of involved nodes was 10. During induction therapy, fever requiring i.v. antibiotics occurred in 4% of 144 courses, 14% of patients suffered from mucositis WHO grade 2-3, and the other patients had mucositis grade 1. During the ablative chemotherapy, 1 patient died, 6 developed septicaemia, 5 showed mucositis grade 3-4 and the other patients had mucositis grade 1 or 2. In the follow-up, 1 patient died from acute cardiac failure. Reversible radiation-induced pneumonitis occurred in 7 out of 14 irradiated patients; symptoms started directly following radiotherapy and lasted for several weeks, but disappeared in due course. During follow-up, 2 patients with six and > 10 positive nodes, respectively, have relapsed after 18 and 36 months, both in the cyclophosphamide/etoposide regimen. Median observation is 3 years, disease-free survival at 5 years is predicted to be 84%. Intensive treatment in these patients with high numbers of involved axillary lymph nodes is a toxic regimen, but may improve the chance of surviving free of disease.

Induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with locally advanced and disseminated breast cancer.

In 56 patients with disseminated or locally advanced breast cancer it was attempted to reach a state of no evidence of disease by a remission induction regime containing prednisone, 5-fluorouracil, methotrexate, doxorubicin and vincristine. If successful, patients received an intensification regimen consisting of cyclophosphamide (7 g/m2) and etoposide (1.5 g/m2) with autologous bone marrow reinfusion. The complete remission rate of the induction regimen was 52% and the partial remission rate 42%. 32 patients received the intensification regimen. Two toxic deaths occurred. The median time to disease progression in the group with disseminated disease was 15 months. After a median observation of 4 years, 11 out of 19 patients with locally advanced breast cancer were free of disease. It is concluded that this approach may lead to prolonged disease-free survival in patients with locally advanced breast cancer, but does not influence the survival in disseminated disease.

Endothelial Damage in Long-Term Survivors of Childhood Cancer

PURPOSE To evaluate the presence of vascular damage in long-term childhood cancer survivors (CCS) and sibling controls, and to evaluate the association between vascular damage parameters and cancer treatment and influence of cardiovascular risk factors. PATIENTS AND METHODS Vascular assessment was performed in 277 adult CCSs (median age at diagnosis, 9 years; range, 0 to 20 years; median current age, 28 years; range, 18 to 48 years) treated with potentially cardiovascular toxic anticancer treatment (ie, anthracyclines, platinum, and/or radiotherapy [RT]). Measurements included carotid- and femoral-wall intima-media thickness (IMT), flow-mediated vasodilatation of the brachial artery by ultrasound, assessment of endothelial and inflammatory marker proteins (including tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor type 1 [PAI-I]), and cardiovascular risk factors. CCS assessments were compared with those of 130 sibling controls (median age, 26 years; range, 18 to 51 years). RESULTS At a median of 18 years (range, 5 to 31 years) after treatment, carotid and femoral IMTs in CCSs were not different from those of controls. However, CCSs who received RT as part of their treatment regimen had increased carotid and femoral IMTs and higher t-PA and PAI-I levels, indicating vascular damage and persistent endothelial activation. Patients treated with RT to the neck or chest also had greater femoral IMT. Greater IMT was associated with presence of cardiovascular risk factors (eg, hypertension and overweight). CONCLUSION After potentially cardiovascular toxic anticancer treatment, CCSs who received RT showed signs of endothelial damage and an unfavorable cardiovascular risk profile compared with controls. CCSs treated with localized RT had increased IMT outside the primary irradiation field. These abnormalities are probably involved in the pathogenesis of cardiovascular morbidity in CCSs.

Cardiotoxicity from intensive chemotherapy combined with radiotherapy in breast cancer

Cardiac function was evaluated in 86 breast cancer patients after standard chemotherapy, followed by ablative chemotherapy and chest irradiation. One patient died of subacute heart failure 3 months after ablative chemotherapy. At a minimum of 1 years follow-up (range 1-11 years) left vertricular ejection fraction (LVEF) was marginally abnormal in 4 of 27 disease-free survivors. One exceptional patient who received two transplantations is alive, with serious heart failure occurring after the second ablative chemotherapy. Including this patient, the percentage of patients free of clinical and subclinical cardiac dysfunction at 7 years is 78% (95% CI 61-95%). After ablative chemotherapy, cardiotoxicity was rarely life-threatening. The impact of subclinical cardiotoxicity in the long term is not clear and needs continued evaluation.

Guideline adherence for early breast cancer before and after introduction of the sentinel node biopsy

This population-based study aimed to analyse variations in surgical treatment and guideline compliance with respect to the application of radiotherapy and axillary lymph node dissection (ALND), for early breast cancer, before and after the sentinel node biopsy (SNB) introduction. The study included 13 532 consecutive surgically treated stage I–IIIA breast cancer patients diagnosed in 1989–2002. Hospitals showed large variation in breast-conserving surgery (BCS) rates, ranging between 27 and 72% for T1 and 14 and 42% for T2 tumours. In multivariate analysis marked inter-hospital and time-dependent variation in the BCS rate remained after correction for case-mix. The guideline adherence was markedly lower for elderly patients. In 25.2% of the patients aged ⩾75 years either ALND or radiotherapy were omitted. The proportion of patients with no ALND after an SNB increased from 1.8% in 1999 to 37.8% in 2002. However, in 2002 also 12.2% of the patients with a positive SNB did not have an ALND. Guideline compliance for BCS, with respect to radiotherapy and ALND, fell since the SNB introduction, from 96.1% before 2000 to 91.4% in 2002 (P<0.001). Noncompliance may however reflect patient-tailored medicine, as for elderly patients with small, radically resected primary tumours. The considerable variation in BCS-rates is more consistent with variations in surgeon preferences than patients choice.

Five year outcomes of hypofractionated simultaneous integrated boost irradiation in breast conserving therapy; patterns of recurrence

In 2005, we introduced hypofractionated 3-dimensional conformal radiotherapy with a simultaneous integrated boost (3D-CRT-SIB) technique after breast conserving surgery. In a consecutive series of 752 consecutive female invasive breast cancer patients (stages I-III) the 5-year actuarial rate for local control was 98.9%. This new technique gives excellent 5-year local control.

Limited benefit of inversely optimised intensity modulation in breast conserving radiotherapy with simultaneously integrated boost

BACKGROUND AND PURPOSE To examine whether in breast-conserving radiotherapy (RT) with simultaneously integrated boost (SIB), application of inversely planned intensity-modulated radiotherapy (IMRT-SIB) instead of three-dimensional RT (3D-CRT-SIB) has benefits that justify the additional costs, and to evaluate whether a potential benefit of IMRT-SIB depends on specific patient characteristics. MATERIAL AND METHODS 3D-CRT-SIB and various IMRT-SIB treatment plans were constructed and optimised for 30 patients with early stage left-sided breast cancer. Coverage of planning target volumes (PTVs) and dose delivered to organs at risk (OARs) were determined for each plan. Overlap between heart and breast PTV (OHB), size of breast and boost PTVs and boost location were examined in their ability to identify patients that might benefit from IMRT-SIB. RESULTS All plans had adequate PTV coverage. IMRT-SIB generally reduced dose levels delivered to heart, lungs, and normal breast tissue relative to 3D-CRT-SIB. However, IMRT-SIB benefit differed per patient. For many patients, comparable results were obtained with 3D-CRT-SIB, while patients with OHB>1.4 cm and a relatively large boost PTV volume (>125 cm(3)) gained most from the use of IMRT-SIB. CONCLUSIONS In breast-conserving RT, results obtained with 3D-CRT-SIB and IMRT-SIB are generally comparable. Patient characteristics could be used to identify patients that are most likely to benefit from IMRT-SIB.

Colorectal Adenomas and Cancers After Childhood Cancer Treatment: A DCOG-LATER Record Linkage Study

Background Although colorectal adenomas serve as prime target for colorectal cancer (CRC) surveillance in other high-risk groups, data on adenoma risk after childhood cancer are lacking. We evaluated the risk of histologically confirmed colorectal adenomas among childhood cancer survivors. A secondary aim was to assess CRC risk. Methods The DCOG-LATER cohort study includes five-year Dutch childhood cancer survivors and a sibling comparison group (n = 883). Colorectal tumors were identified from the population-based Dutch Pathology Registry (PALGA). We calculated cumulative incidences of adenomas/CRCs for survivors and siblings. For adenomas, multivariable Cox regression models were used to evaluate potential risk factors. All statistical tests were two-sided. Results Among 5843 five-year survivors (median follow-up = 24.9 years), 78 individuals developed an adenoma. Cumulative incidence by age 45 years was 3.6% (95% confidence interval [CI] = 2.2% to 5.6%) after abdominopelvic radiotherapy (AP-RT; 49 cases) vs 2.0% (95% CI = 1.3% to 2.8%) among survivors without AP-RT (28 cases; Pdifference = .07) and vs 1.0% (95% CI = 0.3% to 2.6%) among siblings (6 cases) (Pdifference = .03). Factors associated with adenoma risk were AP-RT (hazard ratio [HR] = 2.12, 95% CI = 1.24 to 3.60), total body irradiation (TBI; HR = 10.55, 95% CI = 5.20 to 21.42), cisplatin (HR = 2.13; 95% CI = 0.74 to 6.07 for <480 mg/m²; HR = 3.85, 95% CI = 1.45 to 10.26 for ≥480 mg/m²; Ptrend = .62), a hepatoblastoma diagnosis (HR = 27.12, 95% CI = 8.80 to 83.58), and family history of early-onset CRC (HR = 20.46, 95% CI = 8.10 to 51.70). Procarbazine was statistically significantly associated among survivors without AP-RT/TBI (HR = 2.71, 95% CI = 1.28 to 5.74). Thirteen CRCs occurred. Conclusion We provide evidence for excess risk of colorectal adenomas and CRCs among childhood cancer survivors. Adenoma risk factors include AP-RT, TBI, cisplatin, and procarbazine. Hepatoblastoma (familial adenomatous polyposis-associated) and family history of early-onset CRC were confirmed as strong risk factors. A full benefit-vs-harm evaluation of CRC screening among high-risk childhood cancer survivors warrants consideration.