Erik Wist

2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial

BACKGROUND Trastuzumab--a humanised monoclonal antibody against HER2--has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drugs effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study. METHODS HERA is an international multicentre randomised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer. 5102 women participated in the trial; we analysed data from 1703 women who had been randomised for treatment with trastuzumab for 1 year and 1698 women from the control group, with median follow-up of 23.5 months (range 0-48 months). The primary endpoint of the trial was disease-free survival. Here, we assess overall survival, a secondary endpoint. Analyses were done on an intent-to-treat basis. This trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS 97 (5.7%) patients randomised to observation alone and 58 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up. 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47-0.91; p=0.0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54-0.76; p<0.0001). INTERPRETATION Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years. The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer.

Docetaxel Compared with Sequential Methotrexate and 5-Fluorouracil in Patients with Advanced Breast Cancer after Anthracycline Failure: a Randomised Phase III Study with Crossover on Progression by the Scandinavian Breast Group

The aim of this study was to compare the efficacy and tolerability of docetaxel to methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure. A randomised multicentre trial was conducted in 283 patients with advanced breast cancer who had failed previous anthracycline treatment. Docetaxel at a dose of 100 mg/m2 every 3 weeks (n = 143) was compared with sequential methotrexate and 5-fluorouracil (MF; n = 139) given at day 1 and 8 every 3 weeks at dosages of 200 mg/ m2 and 600 mg/m2, respectively. After progression, crossover to the alternative treatment group was recommended. There was a significantly higher overall response rate in the docetaxel 42% (CR 8% + PR 34%) than in the MF arm 21% (CR 3% + PR 18%) (P < 0.001). The median time to progression (TTP) was 6.3 months in the docetaxel arm and 3.0 months in the MF arm (P < 0.001). Docetaxel also had a significantly higher response rate of 27% following crossover compared with MF (12%). Significantly more side-effects (leucopenia, infections, neuropathy, oedema, asthenia, skin, nail changes, alopecia) were seen in the docetaxel than in the MF group. However, grade 3 and 4 side-effects were infrequent with both drugs, with the exception of fatigue, alopecia and infections. Median overall survival (OS) including crossover phase was 10.4 months in the docetaxel and 11.1 months in the MF arm (P = 0.79). Based on the response rate and the primary endpoint of TTP, docetaxel is superior to sequential methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure.

Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial

BACKGROUND Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. METHODS 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. FINDINGS At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. INTERPRETATION Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.

Phase III Randomized Study Comparing Docetaxel Plus Trastuzumab With Vinorelbine Plus Trastuzumab As First-Line Therapy of Metastatic or Locally Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: The HERNATA Study

PURPOSE To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2-positive advanced breast cancer. PATIENTS AND METHODS Patients naive to chemotherapy for advanced disease were randomly assigned to docetaxel 100 mg/m(2) day 1 or vinorelbine 30 to 35 mg/m(2) on days 1 and 8, both combined with trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance dose) on day 1 every 3 weeks. The primary end point was time to progression (TTP). RESULTS A total of 143 patients were randomly allocated to docetaxel, and 141 patients were assigned to vinorelbine. The median TTP for docetaxel and vinorelbine respectively was 12.4 months versus 15.3 months (hazard ratio [HR] = 0.94; 95% CI, 0.71 to 1.25; P = .67), median overall survival was 35.7 months versus 38.8 months (HR = 1.01; 95% CI, 0.71 to 1.42; P = .98), and the 1-year survival rate was 88% in both arms. Median time to treatment failure for study chemotherapy was 5.6 months versus 7.7 months (HR = 0.50; 95% CI, 0.38 to 0.64; P < .0001). The investigator-assessed overall response rate among 241 patients with measurable disease were 59.3% in both arms. More patients in the docetaxel arm discontinued therapy due to toxicity (P < .001). Significantly more treatment-related grade 3 to 4 febrile neutropenia (36.0% v 10.1%), leucopenia (40.3% v 21.0%), infection 25.1% v 13.0%), fever (4.3% v 0%), neuropathy (30.9% v 3.6%), nail changes (7.9% v 0.7%), and edema (6.5% v 0%) were reported with docetaxel. CONCLUSION The study failed to demonstrate superiority of any drug in terms of efficacy, but the vinorelbine combination had significantly fewer adverse effects and should be considered as an alternative first-line option.

Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer

OBJECTIVE To investigate whether unilaterally orchiectomised testicular cancer survivors (TCSs) are more likely to display reduced Leydig cell function than healthy males. METHODS A national multi-centre survey of 1235 TCSs was performed in 1998-2000 (mean age: 44 years) treated between 1980 and 1994 (mean follow-up: 11 years). Serum hormone analyses were performed on 1183 TCSs, as 52 TCSs used androgen replacement (AR). TCSs were allocated to four treatment groups: Surgery only (251); Radiotherapy only (515); Chemotherapy 1, cisplatin </=850 mg (373); Chemotherapy 2, cisplatin >850 mg (96). The Controls were represented by 200 healthy blue-collar workers (mean age: 44 years). LH >12 IU/l and testosterone <8 nmol/l and the use of AR indicated hypogonadism. RESULTS Serum testosterone was similar in TCSs and Controls (16.9 vs.17.1 nmol/l), but TCSs had higher age-adjusted LH levels than the Controls (5.2 vs. 3.5 IU/l). LH increased with treatment intensity, but was elevated even in TCSs treated with surgery only. The age-adjusted odds ratio of hypogonadism was 3.8 (95%CI: 2.0-7.3) in TCSs, and increased with treatment intensity. CONCLUSION TCSs are at risk to develop pre-mature reduced Leydig cell function and hypogonadism. They may therefore be predisposed for the syndrome of androgen deficiency of aging males (ADAM).

Study of Anxiety Disorder and Depression in Long-Term Survivors of Testicular Cancer

PURPOSE To increase our knowledge of the prevalence of anxiety disorder and depression in long-term testicular cancer survivors (TCSs), and to identify variables associated with such caseness. PATIENTS AND METHODS Participants were 1,408 TCSs treated between 1980 and 1994 in Norway. Participants provided information about their medical, social, and familial situation on a questionnaire. They also completed the Hospital Anxiety and Depression Scale (HADS). Anxiety disorder and depression were defined by a score >/= 8 on the HADS subscales. The prevalence rates were compared with age-adjusted norm data. RESULTS HADS-defined anxiety disorder was more prevalent in TCSs (19.2%; 95% CI, 17.2% to 21.3%) than in the norm sample (13.5%; 95% CI, 13.1% to 13.9%; P < .001), whereas the prevalence of HADS-defined depression did not differ from the norm (TCSs, 9.7%; 95% CI, 8.1% to 11.2% v norm, 10.1%, 95% CI, 9.5 to 10.5; P = .56). The relative risk for anxiety disorder was 1.49 (95% CI, 1.31 to 1.69) and for depression the relative risk was 0.96 (95% CI, 0.81 to 1.14) in TCSs compared with norm. In multivariate analyses, HADS-defined anxiety disorder in TCSs was associated with young age, peripheral neuropathy, economic problems, alcohol problems, sexual problems, relapse anxiety, and having been treated for mental problems. CONCLUSION Long-term TCSs have an increased risk of HADS-defined anxiety disorder that warrants clinical attention. Checking easily available demographic and TC-related data and use of a simple screening test such as HADS assists the identification of TCSs with anxiety disorder.

Cancer patients use of nonproven therapy: a 5-year follow-up study.

PURPOSE To investigate the prospective pattern of use of alternative medicine, here called nonproven therapy (NPT), among oncologic patients during a 5-year period, and the relationship between this use and survival, a questionnaire-based follow-up study was performed at the Department of Oncology, University of Tromsø, from 1990 to 1996. PATIENTS AND METHODS Two-hundred fifty-two patients answered the first questionnaire during the period July 1990 to July 1991. Eligible patients were mailed follow-up questionnaires after 4, 12, 24 and 60 months. A telephone interview performed after the last follow-up questionnaire showed little disagreement with the prospective collected information as regards the number of patients reported as users of NPT (kappa, 0.92). RESULTS The number of patients who reported ever using NPT in each cross-sectional part of the study varied between 17.4% and 27.3%. However, the estimated cumulative risk of being a user of NPT during the follow-up period was 45%. Seventy-four percent of NPT users in this north Norwegian study population used faith healing or healing by hand (spiritual NPT) alone or in combination with other forms of NPT. The proportion of patients who used spiritual versus nonspiritual forms of NPT was consistent throughout the follow-up period. Women were more often users than men (50% v 31%, P = .002). Patients older than 75 years of age seldomly used NPT. The 5-year observed survival rate was not influenced by the use of NPT. Adjusted for sex, age, and diagnosis, patients with a high educational level had a borderline higher 5-year survival rate than patients with less education (P = .06). CONCLUSION Our results demonstrate that cross-sectionally designed studies will underestimate the number of ever-users of NPT in a cancer patient population. The use of NPT does not influence observed survival among cancer patients seen in north Norway.

Fear of recurrence in long-term testicular cancer survivors.

Objective: To explore fear of recurrence (FoR) in long‐term testicular cancer survivors (TCSs) since FoR hardly has been examined in TCSs.

Blood pressure and body mass index in long-term survivors of testicular cancer.

PURPOSE To evaluate blood pressure and body mass index (BMI) in long-term survivors of testicular cancer (TC) treated with different modalities. PATIENTS AND METHODS One thousand eight hundred fourteen patients treated for unilateral TC in Norway (1980 to 1994) were invited to participate in a follow-up study (1998 to 2002), including measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. Of these patients, 1,289 patients (71%) participated in the study. The patients were categorized into four treatment groups: surgery (n = 242), radiotherapy (n = 547), and two chemotherapy groups, cumulative cisplatin dose < or = 850 mg (n = 402) and cumulative cisplatin dose more than 850 mg (n = 98). A control group consisted of healthy males from the Tromsø Population Study (n = 2,847). RESULTS At diagnosis, age-adjusted regression analyses showed no differences between the treatment groups for any variables. After a median follow-up time of 11.2 years, age-adjusted SBP and DBP were significantly higher for both chemotherapy groups compared with the surgery group. Chemotherapy-treated patients had increased odds for hypertension at follow-up compared with the surgery group, and the odds were highest for the cisplatin more than 850 mg group (odds ratio = 2.4; 95% CI, 1.4 to 4.0). The cisplatin more than 850 mg group had a significantly higher 10-year BMI increase and a higher prevalence of obesity at follow-up than the surgery group. Compared with healthy controls, chemotherapy-treated patients had, at follow-up, increased SBP, increased DBP, excessive BMI increase, and a higher prevalence of hypertension. CONCLUSION Five to 20 years after therapy, cured TC patients treated with cisplatin-based chemotherapy had significantly higher levels of blood pressure, a higher prevalence of hypertension, and an excessive weight gain compared with patients treated with other modalities and compared with healthy controls.

Observational Study of Prevalence of Long-term Raynaud-Like Phenomena and Neurological Side Effects in Testicular Cancer Survivors

Background Sensory neuropathy (paresthesias), tinnitus, hearing impairment, and Raynaud phenomena are side effects of cisplatin-based chemotherapy used to treat testicular cancer patients. We assessed the long-term occurrence of these side effects among testicular cancer survivors according to the treatment they received. Methods A total of 1814 men who were treated for unilateral testicular cancer in Norway during 1980–1994 were invited to participate in a national multicenter follow-up survey conducted during 1998–2002. The men were allocated to six groups according to the treatment they had received. Self-reported symptoms were assessed by a mailed questionnaire that included the Scale for Chemotherapy-Induced Neurotoxicity. A total of 1409 participants who responded to the questionnaire and/or underwent audiometry were assessable in this study. Respondents to the questionnaire (n = 1402) scored the relevant symptoms according to how troubled they were by each (not at all, a little, quite a bit, or very much). Hearing impairment was objectively assessed by audiometry at 4000 Hz in 755 men (seven of whom did not respond to the questionnaire). Group comparisons of symptom assessments were performed with χ2 or Kruskal–Wallis tests. Associations between relevant factors and self-reported symptoms or hearing impairment measured by audiometry were assessed using proportional odds ordinal logistic regression models and linear regression models, respectively. All statistical tests were two-sided. Results The median follow-up for the 1409 assessable men was 10.7 years (range = 4–21 years). All chemotherapy groups had statistically significantly higher odds for increasing severity of all assessed symptoms and inferior audiometric results compared with men who did not receive chemotherapy. Among chemotherapy-treated men, 39% (95% confidence interval [CI] = 35% to 43%) reported Raynaud-like phenomena (defined as white or cold hands or fingers [or feet or toes] on cold exposure), 29% (95% CI = 25% to 33%) reported paresthesias in the hands or feet, 21% (95% CI = 18% to 25%) reported hearing impairment, and 22% (95% CI = 19% to 26%) reported tinnitus as major symptoms troubling them quite a bit or very much. Hearing impairment (odds ratio [OR] = 5.3, 95% CI = 3.0 to 9.2) and tinnitus (OR = 7.1, 95% CI = 4.1 to 12.4) were particularly common in the dose-intensive chemotherapy group compared with the no chemotherapy group. Men who were treated with radiotherapy had higher odds of self-reported paresthesias in feet compared with those not treated with radiotherapy (OR = 1.5, 95% CI = 1.01 to 2.1, P = .04). Conclusion Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy were more often troubled by dose-dependent neurological side effects and Raynaud-like phenomena compared with those who were not treated with chemotherapy.