Lionel Vedrine

Tomorrow's targeted therapies in breast cancer patients: What is the risk for increased radiation-induced cardiac toxicity?

Ongoing clinical trials are now investigating the benefits of new targeted therapies, including ErbB and tyrosine kinase inhibitors (TKI) and antiangiogenics. Those may carry a potential risk for additional cardiac toxicity, particularly in association with radiotherapy. Although the risk of symptomatic cardiotoxicity is low, more subtle functional declines may increase mortality with longer follow-up and necessitate caution when assessing concurrent or sequential trastuzumab or lapatinib with radiotherapy. Potential additive toxicity encourages more conformal irradiation modalities minimizing cardiac dose, such as gating, intensity-modulated radiotherapy or Helical Tomotherapy. We recommend the collection of substantial information relevant to cardiac radiotoxicity in further clinical trials of targeted agents in breast cancer treatment, including doses delivered to cardiac structures, especially the coronary arteries. The incorporation of new biomarkers or modalities for assessment of cardiac function may also become necessary to detect cardiac toxicity at earliest stage.

Impact on Cardiac Toxicity With Trastuzumab and Radiotherapy: The Question Is Still Ongoing

TO THE EDITOR: In a recent issue of Journal of Clinical Oncology, Halyard et al retrospectively examined adverse events data from the North Central Cancer Treatment Group phase III trial N9831 and directly evaluated the effect of trastuzumab on radiation-induced cardiac toxicity. At a median follow-up of 3.7 years, radiotherapy concurrently with trastuzumab did not increase relative frequency of cardiac events, regardless of treatment side, suggesting that concurrent adjuvant radiation therapy and trastuzumab was not associated with increased acute adverse events. To our knowledge, the cardiac effects of the interaction of trastuzumab and radiation therapy had not been reported before, and this content-rich article is one of the best pieces of literature that elaborates on the cardiac toxicity of concurrent use of trastuzumab and radiation therapy. However, several shortcomings are present and should be highlighted. Firstly, there is a need to focus not only on severe symptomatic cardiac disease. Subtle functional declines and minor cardiovascular changes may also increase mortality with longer follow-up. Unchanged value in left ventricular ejection fraction is not equated to a lack of cardiotoxicity and additional strategies for the monitoring of radiation-induced cardiotoxicity are being explored. Secondly, strategies involving concurrent targeted therapies and radiotherapy should be considered in randomized trials in which every effort should be made to minimize the dose to the heart. A substantial amount of relevant information should be required in further clinical trials, including doses delivered to cardiac structures, especially the coronary arteries. This information would be of first importance. Finally, preliminary experiences with trastuzumab suggest a need for continued cardiac follow-up. Close attention to the long-term cardiovascular adverse effect profile of targeted agents is imperative during their clinical development, particularly when evaluating combinations of new agents with radiotherapy and/or chemotherapy.

Prostate needle biopsy examination by means of virtual microscopy

This study aimed at determining whether virtual microscopy improves the accuracy in the pathological examination of prostate needle biopsies regarding maximum tumor length, percentage of positive cores, and Gleason grading. We assessed a series of 816 prostate needle biopsy cores in 68 consecutive patients with prostate adenocarcinoma. Biopsy specimens were reviewed using conventional examination. Then, slides were converted to whole slide imaging (Olympus BX51). Tumor was measured, and Gleason score was assigned using the OlyVia software. Optically evaluated pathological features were compared with digital findings to determine whether one of these two methods for the assignment of a preoperative Gleason score is appropriate for predicting the definitive Gleason score of radical prostatectomy. When comparing optical and digital measurements, maximum tumor length in biopsy cores and percent prostate needle biopsy with cancer showed no significant difference. The mean variation in the measurement of tumor length was 2.65mm per biopsy. Among 240 biopsy cores involved with cancer, the concordance rate for Gleason score assignment was 75.8% (κ=0.49, good agreement). When considering the higher Gleason score assignment as the score for the entire case (ISUP 2005), the concordance rate was 69.1% (κ=0.46, good agreement). When comparing the biopsy scores with the definitive score of radical prostatectomy, the concordance rate was significantly increased from 54.4% for conventional examination (κ=0.23, marginal agreement) to 66.2% for virtual slide examination (κ=0.42, good agreement). Virtual microscopy does not compromise, but might improve, the accuracy of grading in prostate needle biopsies. This requires further assessment.

Reapprasial of the role of endocrine therapy in meningioma management

Recurrent meningiomas constitute an uncommon but significant problem after standard therapy failure. Speculation that meningiomas may be subject to endocrine influence was supported by both immunohistochemical analyses and epidemiological data. Therefore, alternative strategies such as endocrine therapy have been suggested. Although evidence of consistent findings for the role of specific hormonal exposures is mounting, there are numerous discrepancies about the mitogenic effect of hormonal manipulation on meningioma cells. A better understanding of the molecular mechanisms involved in meningioma pathogenesis may not only lead to the identification of novel diagnostic and prognostic markers but may also facilitate the development of new pathogenesis-based targeted strategies. This review of literature aims to summarize the present state of the art of endocrine therapy in the management of meningiomas, in order to establish whether hormonotherapy could be included in the therapeutic strategy for unresectable and/or progressive tumours in previously irradiated meningioma patients.

Impact of radiotherapy on fertility in female patients

Although insufficiently documented, the impact of radiation therapy on fertility should not be neglected in female patients. Toxicity on reproductive function is dual and is characterized by both mechanistic deleterious effects on the genital tract and partial or complete loss of ovarian function. Moreover, gonadic toxicity may be increased by the concurrent use of chemotherapy or surgical procedure. In some circumstances, ovarian transposition may be justified for young patients. But no compromise may be accepted in terms of carcinologic results. At least, the effect of low-doses of irradiation has not been demonstrated for extra-pelvic radiotherapy.

Symptomatic solitary skull bone metastasis as the initial presentation of a testicular germ cell tumor

In testicular germ cell tumors (GCT), bone metastases are usually seen as a late event. No more than 1% of patients suffer from bone metastases at the time of diagnosis. If present, bone metastases are almost always associated with diffuse metastatic disease at other sites. Here we report a case of acute hemiparesis due to solitary skull bone metastasis as the presenting symptom of a testicular GCT. A 44-year-old patient presented with acute left hemiparesis and progressive skull tumefaction. Physical examination revealed swelling of the right frontal region of the skull, measuring more than 10 cm in greatest dimension. Physical examination revealed a nodular mass of the left testis, measuring four centimeters in greatest dimension. Brain magnetic resonance imaging (MRI) revealed a 55 ¥ 50 ¥ 50-mm tumor mass originating from the frontal bone, with spread into the brain by infiltration of dura mater and of the superior longitudinal sinus, with a mass effect (Fig. 1). Thoracicabdominal CT showed a left testicular mass. Bone scintigraphy revealed pathological technetium uptake at the site of the skull mass and showed no other bone lesions. Left inguinal orchiectomy was performed. Microscopic pathological examination revealed the presence of a mixed nonseminomatous GCT, with 90% yolk sac tumor, and presence of 10% seminoma component. The primary tumor was staged pT1. A biopsy of the skull mass confirmed the diagnosis of isolated bone metastasis in the testicular yolk sac tumor. Postoperative laboratory evaluation revealed an alpha fetoprotein of 478 ng/mL (normal <10 ng/mL). Following orchiectomy, bleomycin, etoposide and cisplatin (BEP) chemotherapy was administered. After three cycles, brain MRI demonstrated the persistence of an osteolysis of the right frontal bone, measuring 32 mm in greater dimension, with residual contrast enhancement.After the fourth cycle, surgery of the residual skull mass was planned and craniectomy was performed. Pathological examination demonstrated complete response. Twelve months later, the patient remains disease-free and asymptomatic. GCT with distant visceral involvement usually has a nodal pattern, spreading from the testis sequentially to paraaortic lymph nodes, then ultimately to extranodal sites of distant metastases. Almost all patients with nonpulmonary metastases present with lymph node metastases. The mechanisms of the development of isolated bone metastases are uncertain and debated. There is growing evidence that tumor cells may potentially spread hematogenously to the skull passing the lungs via the vertebral venous system. Bone metastases are almost always diagnosed very late in the disease progression. Most cases are recurrences following initial treatment for a GCT and occur in the spine. Only one case was a skull metastasis from nonseminomatous GCT as the initial manifestation. Patients should be treated with curative intent and systemic chemotherapy delivery should be considered as an oncological emergency. In the management of extensive local tumor associated with increased intracranial pressure, chemotherapy provides rapid relief of neurological symptoms. Surgical removal of the residual mass should be proposed in a patient with a solitary tumor site and partial response following chemotherapy.

Le growing teratoma syndrome

Growing teratoma syndrome (GTS) is a rare entity, characterized by enlarging masses of the retroperitoneum or other location occurring during or after systemic chemotherapy for the treatment of non-seminomatous germ cell of the testis (NSGCT). Three criteria define this syndrome: enlarging metastatic masses, normalized serum markers and no component of viable germ cell tumor in this mature teratoma. Prognostic is excellent after the resection of these masses, but this surgery has to be as much complete as possible. Surgical excision of large GTS lesions is technically challenging, a serious intraoperative complications may occur, thats why the treatment must not be delayed.

Pancreatic Metastasis from Prostate Cancer

The pancreas is an unusual location for metastases from other primary cancers. Rarely, pancreatic metastases from kidney or colorectal cancers have been reported. However, a variety of other cancers may also spread to the pancreas. We report an exceptional case of pancreatic metastasis from prostate cancer. Differences in management between primary and secondary pancreatic tumors make recognition of metastases to the pancreas an objective of first importance. Knowledge of unusual locations for metastatic spread will reduce diagnostic delay and lead to a timely delivery of an appropriate treatment.

Mécanismes de résistance aux thérapeutiques moléculaires ciblées dans le cancer du sein : constats et perspectives

The importance of targeted therapies has been emphasized by clinical trials using antiangiogenic or HER2 inhibitors in breast cancer. First with trastuzumab, it was demonstrated that targeted therapies may improve outcome in patients with HER overexpressing breast cancer in metastatic or adjuvant settings. The emerging role for angiogenesis inhibitors has also been demonstrated with bevacizumab. Unfortunately, there is growing clinical and biological evidence that tumour cells may develop unexpected and complex mechanisms of resistance to those targeted therapies. This review outlines the mechanisms by which tumour cells may resist to new targeted agents. Most recent developments are also highlighted.

Métastase testiculaire d’un adénocarcinome prostatique : à propos d’un cas

Resume Le cancer de la prostate est exceptionnellement responsable d’un envahissement metastatique testiculaire. En cas de suspicion clinique, I’orchidectomie est indispensable. Elle permet la confirmation histologique du diagnostic et elimine une autre origine primitive. L’attitude therapeutique ulterieure s’integre dans le cadre de la prise en charge globale de la maladie prostatique metastatique. Nous rapportons l’observation d’un patient de 62 ans porteur d’un adenocarcinome prostatique metastatique au testicule.