Moshe Inbar

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

Summary Background For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. Methods In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Findings Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). Interpretation For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. Funding Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study

Purpose: To assess the efficacy of gemcitabine in patients with a variety of sarcomas that have failed to respond or escaped Adriamycin- and ifosfamide-based chemotherapy. Patients and methods: A group of 18 symptomatic heavily pretreated patients with sarcomas of bone or soft tissue received one induction course of gemcitabine at a dose of 1000 mg/m2 per week for 7 consecutive weeks, followed by 1 week rest. Response to the induction course was assessed by interview and by repeated ancillary tests. If no progression was observed, maintenance by gemcitabine 1000 mg/m2 per week for 3 weeks every 28 days was given until failure was clinically or radiologically evident. Results: A total of 51 cycles of gemcitabine were given including 18 cycles of induction. A mean of 3.6 postinduction cycles were given to nine patients. The treatment was well tolerated by the patients. One partial response (leiomyosarcoma) and one minimal response (angiosarcoma) were observed, yielding a true objective response rate of 5.5%. An additional six patients achieved stabilization of disease (chondrosarcoma and osteosarcoma), yielding an overall progression-free rate of 44%. The median time to progression was more than 27 weeks. Clinical benefit response was observed only in those who also achieved a progression-free state. Conclusion: Gemcitabine was found to be effective in achieving stabilization and even a minimal response of soft tissue or bone sarcoma refractory to standard chemotherapy.

Are malignant melanoma patients at higher risk for a second cancer

This study tests whether malignant melanoma (MM) patients are at higher risk of having an unrelated second cancer by comparing the observed incidence of a second cancer in a given population of MM patients with the expected number in an age‐matched and sex‐matched group of healthy people followed for a similar period. The analysis was based on the person‐years method in which the main consideration is the follow‐up period after the diagnosis of MM. Of 370 patients with histologically confirmed MM, 27 (7.3%) had a second noncutaneous invasive cancer, diagnosed either simultaneously (within 6 months, five patients) or after the diagnosis of MM (22 patients). The follow‐up period for the entire MM group was 1253 person‐years, a period during which the expected number of cancer cases in the normal population, according to the Israel Cancer Registry, was 6.6. The observed–expected ratio or the relative risk (RR) was 4.1 (P less than 0.01). After excluding the five patients with simultaneous diagnosis of MM and a second cancer, analysis of the remaining 22 patients in whom MM definitely preceded the second cancer showed an RR of 3.3 (P less than 0.01). For the entire group, there were nine patients with breast cancer, five with head and neck cancer (two with thyroid and three with oral cavity cancer), five with gynecologic cancer (one with uterine and four with ovarian cancer), five myeloproliferative malignancies (one with lymphoma, three with chronic lymphocytic leukemia, and one with myeloma), three gastrointestinal carcinomas (two with colon and one with stomach cancer), and two soft tissue sarcomas. When the differential analysis according to gender and age was done, it was found that the RR was higher for women (5.5, P less than 0.01) than for men where the RR was 2.2 (P less than 0.05). Differential analysis for various age groups showed that the trend for second cancer was consistent in all age groups, with a slight increase in the younger ones. None of the variables of MM, such as location of the primary tumor, level of invasion, or stage, were predictive for a second cancer. Furthermore, the RR for a second cancer did not relate significantly with the treatment given to the MM patient. Concerning the type of second cancer, it was found that the RR was especially high for breast cancer–‐6.6. These data indicate that MM patients may be at higher risk for having a noncutaneous invasive cancer compared with the general population.

ErbB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti-cancer therapy.

Clinical and experimental data suggest that ErbB‐4, a member of the epidermal growth factor receptor family, may have a role in cancer progression and response to treatment. We found recently, using a retrospective clinical analysis, that expression of ErbB‐4 receptor is correlated with metastatic potential and patient survival in non‐small‐cell lung cancer (NSCLC). The purpose of this work was to correlate the expression of the ErbB‐4 and lung cancer cells growth in vitro and in vivo and to determine the therapeutic potential of a monoclonal antibody to ErbB‐4 against lung cancer. For this aim, we ectopically expressed ErbB‐4 in a human NSCLC cell line that did not express the ErbB‐4 protein. Overexpression of ErbB‐4 produced a constitutively activated ErbB‐4 receptor. The transfected ErbB‐4 positive clones showed an increased cell proliferation in vitro and in vivo in comparison with parental ErbB‐4 negative cells and with the cells transfected by neomycin‐resistant gene. A monoclonal antibody to ErbB‐4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB‐4. The results of the current study provide evidence that ErbB‐4 plays a significant role in human lung cancer and may serve as a molecular target for anticancer therapy.

Primary papillary serous carcinoma of the peritoneum in a man

BACKGROUND Primary papillary serous carcinoma of the peritoneum is a well-known entity in women. The tumour is derived from the extraovarian mesothelium and the pelvis and lower abdomen mesothelia. The treatment strategies are similar to ovarian serous papillary carcinoma. PATIENTS AND METHODS A case of primary serous papillary carcinoma of the peritoneum in a man is presented. The patient, 53 years old, died 2 months after diagnosis. RESULTS The histologic and immunohistochemical studies of the tumour will be presented. These studies, made during lifetime and at autopsy of the patient, confirm a diagnosis of primary serous papillary carcinoma of the peritoneum. CONCLUSIONS primary serous papillary carcinoma of the peritoneum can occur in men, and should be considered in the differential diagnosis in cases of abdominal carcinomatosis of unknown origin. Treatment options remain to be determined.

Palliative Major Amputation and Quality of Life in Cancer Patients

Limb sparing surgery has replaced the amputation surgery in the treatment of limb sarcomas. Recurrent or persistent disease constitutes a major problem. Local symptoms such as agonizing pain, fractures, tumor fungation, inability to walk and inability to maintain daily activities, further impair the patients quality of life. In this clinical set-up palliative amputation should be considered. Eighteen patients with soft-tissue or bone sarcomas and 3 patients with metastatic carcinoma underwent palliative major amputation. Hemipelvectomy was performed in 3 patients, hip disarticulation in 10, knee disarticulation or below-knee amputation in 3 patients, shoulder disarticulation in one patient and forequarter amputation in 4 patients. Local control of the disease and pain and improvement of the performance status were observed in 19 evaluable patients. The mobility was restored in 15 patients with lower limb surgery. The median survival following the procedure was 9 months. There was only one case of immediate post-operative death. Severe phantom pain was not reported by any of the patients. Quality of life was reported to be improved by two-thirds of the patients. To conclude, we have, found palliative major amputation surgery worth performing in low-performance status cancer patients with locally advanced disease.

Is forequarter amputation justified for palliation of intractable cancer symptoms

Background: Limb-sparing surgery has replaced the radical surgical approach for treating limb sarcomas in most cases. Amputation has been advocated as a palliative procedure for symptomatic locally advanced disease that has already failed to respond to radiation therapy, chemotherapy and limited surgery. Methods: Twelve patients with advanced malignant tumors involving the shoulder girdle or the proximal humerus underwent forequarter amputation (FQA) for palliative purposes. The tumor-related local problems were severe pain, limb dysfunction, tumor fungation, bleeding (requiring emergency FQA in one case) and infection. The preoperative Karnofsky performance status (KPS) in our series ranged from 30 to 70%. Results: No perioperative mortality was observed. The morbidity was well tolerated by the patients. The KPS improved in most of the patients, and was assessed as 90–100% in 9 of the 12 patients. Overall, quality of life was reported to be at least moderately improved by 2 out of 3 patients. Survival was measured in months (3–24 months), but ultimately had no meaning since the procedure was palliative. Lung metastases were the dominant cause of death in our patients. Conclusions: The results of FQA in our series point to its feasibility and the gain in quality of life and performance status in severely ill patients with advanced malignancies. Local symptoms and signs were controlled, and quality of life was restored.

The effects of tamoxifen treatment on the endometrium

OBJECTIVE To investigate the association between tamoxifen and endometrial cancer. BACKGROUND Tamoxifen is a nonsteroidal antiestrogenic drug that has been used successfully for 15 years in the treatment of all stages of breast carcinoma. In light of the positive results, several studies are now being conducted to test prolonged tamoxifen treatment as a prophylaxis against breast cancer in high-risk women. Although tamoxifen was thought to have only a few side effects, reports indicate that it is associated with an increased incidence of proliferative and neoplastic changes in the endometrium. As the current trend is to administer tamoxifen for prolonged periods and for more indications, the detrimental effects on the endometrium have vast implications. METHODS Review of the current literature. RESULTS Tamoxifen treatment is associated with an increased incidence of proliferative and neoplastic changes in the endometrium, with a 1.3 to 7.5 relative risk of developing endometrial carcinoma. CONCLUSIONS The results of tamoxifen treatment in breast carcinoma override the risk of developing endometrial carcinoma. Any vaginal bleeding in women treated with tamoxifen should be investigated carefully and promptly. In the future it may be necessary to advise these women to undergo routine uterine cavity examination.

Radiation Therapy of Metastatic Spinal Cord Compression. Multidisciplinary team diagnosis and treatment

Purpose: To evaluate the effectiveness of a multidisciplinary approach to spinal cord compression (SCC) in accordance with prospective protocol, providing a uniform approach to diagnosis, decision making concerning optimal treatment modality in any particular case of SCC, treatment performance and evaluation of treatment results. The SCC patients treated by radiation therapy are described.Materials and Methods: Patients with SCC were examined and treated by a multidisciplinary team consisting of a neurologist, radiologist, oncologist, orthopedic surgeon, and neurosurgeon. Seventy-nine patients for whom radiation was recommended received a 30 Gy radiation dose to a compression-causing mass and course of high dose dexamethasone. Three fractions of 5 Gy and 5 fractions 3 Gy each were delivered by Co60 or 8 MV photon beam in 12 days. Treatment outcome was essentially evaluated by ambulation capabilities which were considered to be the main problem of SCC. Changes in other neurologic motor, sensory and autonomic disturbances were also evaluated.Results: Seventy-two percent of the patients were already non-ambulatory at diagnosis. The first symptom was motor deficiency in only 33% of them while in all other cases it was pain. Ambulation capability was the main prognosticator of treatment outcome; 90% of patients who were ambulatory before treatment remained so while 33% of the non-ambulatory patients regained their ability to walk. The grade of motor disturbance was also an important variable: among the non-ambulatory patients, 50% of the paretic but only 14% of the plegic ones became ambulatory. Overall, 51% of the study patients were ambulatory after undergoing radiation. The ambulatory state after treatment was the main predictor for survival.Conclusion: Close cooperation of a multidisciplinary team in diagnosis and treatment according to the above protocol enabled the achievement of good results of radiation treatment in SCC. Early diagnosis and early treatment should further enhance therapeutic outcome.

Can Rectal Cancers With Pathologic T0 After Neoadjuvant Chemoradiation (ypT0) Be Treated by Transanal Excision Alone

BackgroundPatients with rectal cancer who have complete rectal wall tumor regression after neoadjuvant chemoradiation probably have eradication of tumor cells in the mesorectum as well, thus raising the possibility of transanal excision.MethodsAll pathology reports of all patients with locally advanced low and mid rectal cancer who underwent preoperative chemoradiation followed by radical resection from May 2000 to June 2004 were reviewed to evaluate the correlation between complete tumor response (ypT0) and nodal response.ResultsOne hundred one consecutive patients had neoadjuvant chemoradiation followed by definitive operation. Four were excluded, leaving 64 men and 33 women (median age, 62 years). Fifty-three patients (55%) had mid rectal cancer, and 44 (45%) had low rectal cancer. Fifty-eight patients (60%) underwent low anterior resection, and 36 (37%) underwent abdominoperineal resection. In 17 patients (18%), no residual tumor cells were present within the rectal wall. One patient (6%) with ypT0 disease had positive lymph nodes.ConclusionsNo residual tumor in the rectal wall correlates with the absence of viable cancer cells in the mesorectal tissue (94%). Approximately 10% of T1 tumors have involved lymph nodes, and local excision is an accepted option. Transanal excision could probably be considered in a highly selected group of patients with a mural pathologic complete response to neoadjuvant therapy. This approach should be prospectively investigated, and strict selection guidelines should be used.