Hippocampal avoidance in prophylactic cranial irradiation for small cell lung cancer: benefits and pitfalls

Small cell lung cancers (SCLC) are a group of cancers that are clinically and pathologically different from other lung cancers. They are associated with high recurrence rates and mortality, and many patients present with metastatic disease. Approximately ten percent of SCLC patients have brain metastases at time of diagnosis, and the cumulative incidence of brain metastases increases to more than fifty percent at two years, even with optimal treatment. Hence, in patients without brain metastases at presentation, prophylactic cranial irradiation (PCI) is an important component of treatment along with systemic chemotherapy and radiotherapy. The goal of PCI is to decrease the incidence of subsequent symptomatic brain metastases in patients who show an initial response to the systemic treatment. Various clinical trials have evaluated the utility of PCI and found substantial benefit. Unfortunately, the long-term toxicity associated with PCI, namely the neuro-cognitive impairment that may develop in patients as a result of the radiation toxicity to the hippocampal areas of the brain, has raised concern both for patients and their treating physicians. Various techniques have been tried to ameliorate the neuro-cognitive impairment associated with PCI, including pharmacological agents and highly conformal hippocampal avoidance radiation. All of these have shown promise, but there is a lack of clarity about the optimal way forward. Hippocampal avoidance PCI appears to be an excellent option and a number of groups are currently evaluating this technique. Although there is clear benefit with this specialized radiation treatment, there are also concerns about the risk of disease recurrence in the undertreated hippocampal areas. This review attempts to compile the available data regarding the benefits and pitfalls associated with hippocampal avoidance PCI in the setting of SCLC.     

Advances in understanding of colorectal liver metastasis and implications for the clinic

Colorectal cancer is one of the most common cancers in both the USA and Europe. Over the course of diagnosis, treatment and surveillance, up to 50% of these patients will develop metastases to their liver. In the past 20 years alone, there have been multiple advances in the management of these colorectal metastases to the liver. These advances have been made in characterization of these tumors, diagnosis and in treatment, both locally and systemically. Because of this progress, there are subsets of patients with this stage IV disease who are cured of their disease. While significant progress has been made, there still exist limitations in the management of metastatic colorectal cancer to the liver. This review outlines current strategies and highlights recent advances in the management of colorectal liver metastases.     

Targeting the immune milieu in gastrointestinal cancers

Gastrointestinal (GI) cancers are among the most common and lethal solid tumors worldwide. Unlike in malignancies such as lung, renal and skin cancers, the activity of immunotherapeutic agents in GI cancers has, on the whole, been much less remarkable and do not apply to the majority. Furthermore, while incremental progress has been made and approvals for use of immune checkpoint inhibitors (ICIs) in specific subsets of patients with GI cancers are coming through, in a population of ‘all-comers’, it is frequently unclear as to who may benefit most due to the relative lack of reliable predictive biomarkers. For most patients with newly diagnosed advanced or metastatic GI cancer, the mainstay of treatment still involves chemotherapy and/or a targeted agent however, beyond the second-line this paradigm confers minimal patient benefit. Thus, current research efforts are concentrating on broadening the applicability of ICIs in GI cancers by combining them with agents designed to beneficially remodel the tumor microenvironment (TME) for more effective anti-cancer immunity with intention of improving patient outcomes. This review will discuss the currently approved ICIs available for the treatment of GI cancers, the strategies underway focusing on combining ICIs with agents that target the TME and touch on recent progress toward identification of predictors of sensitivity to immune checkpoint blockade in GI cancers.

     

From suspicion of liver metastases to the diagnosis of Wilson disease in a patient with seminoma

Wilson disease is an autosomal recessive disorder characterized by copper accumulation in the liver, brain, kidneys, and cornea due to inadequate biliary copper excretion. It should be considered especially in young patients who have findings of liver disease with unexplained etiology. Clinical presentation of the disease can be variable, and different types of parenchymal changes of the liver can be seen on imaging modalities. Multiple nodular lesions mimicking metastases can be detected. This condition can obligate physicians to screen for a malignant disease. Moreover, it may cause misdiagnosis as advanced stage of disease when coexistent with a malignancy. The coexistence of Wilson disease with some malignant diseases has been reported; however, coexistence with seminoma was not reported before. Approximately 40% of testicular cancers are pure seminoma. Liver metastases are rare in seminoma. In this article, a case of Wilson cirrhosis is reported. The patient was first followed with diagnosis of seminoma with suspicion of liver metastases.     

Frequent brain metastasis after chemotherapy and surgery for advanced esophageal cancers

BACKGROUND/AIMS: Brain metastasis, rarely observed as a tumor recurrence after curative surgery for thoracic esophageal cancers (TEC), has been increasingly observed with improvement of the clinical outcome of TEC. METHODOLOGY: Records of 254 TEC patients who developed recurrent cancers after curative surgery during 1984-2002 revealed 11 patients (4.3%) with symptomatic brain metastasis, which were classified as five without extra-cranial disease (Brain type) and six with other metastatic diseases (Systemic type). RESULTS: Brain metastases were significantly associated with an advanced clinical stage and perioperative chemotherapy, which had been undergone by 73% of the brain metastasis patients, but only 23% for non-brain metastasis patients (p = 0.0008). Comparing to Systemic type, Brain type showed longer duration from esophagectomy to brain metastasis and tended to be more effective for perioperative chemotherapy. All Brain type but only two Systemic type brain metastases were removed by surgery. The average survival after brain metastasis was 17.7 months for the Brain type patients (two alive without tumor recurrence), but only 38.5 days for the Systemic type patients. The histological hallmark of Brain type metastasis was medullary tumor growth with mature tumor vessels, while Systemic type showed invasive tumor growth with naive capillaries. CONCLUSIONS: Postoperative brain metastasis in TEC patients is not rare, especially in an advanced clinical stage following perioperative chemotherapy. Surgical removal of brain metastasis might be the most promising treatment unless tumor metastasis in other organs is evident.     

以脑转移症状为首发表现的老年肺癌36例临床分析

目的探讨以脑转移为首发表现的老年肺癌的临床特点。方法分析１９８６～１９９６年收治的以脑转移症状为首发表现的３６例老年肺癌患者。结果腺癌、小细胞肺癌较鳞癌多，外周型肺癌远多于中央型，非手术组中位生存期５个月，手术组中位生存期１４个月，误诊率达７７．８％。结论本形式肺癌误诊率高，预后差，放疗、化疗有一定帮助，脑转移病灶能手术切除的患者预后相对较好     

Gastrointestinal malignancies and cardiovascular diseases--non-negligible comorbidity in an era of multi-antithrombotic drug use

Nowadays, antiplatelet and anticoagulant drug medications are indicated in patients with a variety of cardiovascular disorders, such as atrial fibrillation, coronary artery disease, and peripheral artery disease. Among cardiology patients, regardless of gastrointestinal (GI) protection, we do not infrequently encounter those patients who have signs and symptoms that are suggestive of GI tract problems. We should bear in mind that such GI signs and symptoms may be attributed to GI cancers, as well as to benign or clinically insignificant lesions. Several clinical studies have shown, albeit controversially that the predictive value of positive fecal occult blood for colorectal malignant neoplasm may not be lower in patients taking antithrombotic medication. In addition, it has been shown that in patients taking antithrombotic drug(s), diagnosed colorectal malignancies are in a relatively earlier phase, suggesting that antithrombotic drugs may facilitate the detection of otherwise unrecognized cancers. The possibility also exists that certain cardiovascular disease may be associated with a higher risk of GI malignant neoplasms. There has been no established evidence concerning whether more aggressive GI tract screening will reduce the probability of cancer death in cardiology patients; nevertheless, GI tract lesions should not be overlooked among cardiology patients, especially when unexplained anemia, gastrointestinal symptoms, or positive fecal occult blood test is present, and GI tract screening should be performed with appropriate timing.     

Gastrointestinal disease and the kidney

Renal disease at any stage, from insufficiency to end-stage renal disease requiring dialysis or following renal transplantation, is often accompanied by significant gastrointestinal (GI) symptoms. Conversely, patients with GI disease may present with significant renal complications. Patients with end-stage renal disease, patients undergoing dialysis, and recipients of renal grafts are at increased risk for GI complications, including erosive disease and GI bleeding. Selection of pharmacotherapy for GI conditions in patients with concomitant renal disease is complicated by three factors: (1) the potential for a significant negative impact on renal function, which is already compromised; (2) the requirement for dosing alteration in renal insufficiency; and (3) the potential for drug-drug interactions with concomitant medications. Proton pump inhibitors appear to be the most suitable acid-suppressing therapy for patients with renal disease; recently developed drugs in this class (e.g. rabeprazole) may be the best choice for treatment of patients with both acid-related GI conditions and renal disease.     

Liver transplantation for the treatment of neuroendocrine liver metastases

Neuroendocrine neoplasms represent a heterogeneous group of cancers arising from a variety of neuroendocrine cell types. In general, these tumors (NET) are asymptomatic and are discovered late once metastatic disease is present (40–80%). The liver is the most common organ involved when metastases occur (40–93%), followed by bone (12–20%) and lungs (8–10%). A number of different therapeutic options are available for patients with hepatic metastases including surgical resection, transplantation, transarterial chemoembolization, radiofrequency and microwave ablation, radioembolization (Y90), chemotherapy, somatostatin analogues and molecular targeted therapies. Surgical resection is still considered the treatment of choice and provides excellent disease control with an overall survival of 47–92%. Liver transplantation has been advocated in selected patients with bilateral unresectable symptomatic liver metastases. The aim of this study is to review the existing literature emphasizing on the role of transplantation to treat patients with liver metastases from NET.     

Effect of chemotherapy on survival after whole brain radiation therapy for brain metastases: a single-center retrospective analysis

Background and purpose

Whether chemotherapy for systemic disease affects survival of patients with brain metastases or not has not been elucidated before. We performed comprehensive analysis of patients with newly-diagnosed brain metastases primarily treated with whole brain radiation therapy (WBRT) alone.

Materials and methods

Data from 134 patients with newly-diagnosed brain metastases primarily treated with WBRT from 2007 to 2008 was retrospectively reviewed. Univariate and multivariate analyses were performed to identify significant prognostic factors.

Results

Median survival time (MST) of this cohort from the start of WBRT was 5.7?months. MST of patients with RPA Class 1, 2 and 3 were 10.3, 7.8 and 2.2?months, respectively. Multivariate analysis revealed that karnofsky performance status (≥70, p?p?p?=?0.015), time to develop brain metastasis (<3?months, p?=?0.042) and use of chemotherapy after WBRT (multiple regimens, p?Conclusions Systemic chemotherapy for chemo-responsive cancer prolongs survival despite the presence of treated brain metastases. Irradiated brain metastases will lose their prognostic significance in a large number of patients. Systemic chemotherapy will be a treatment of choice for patients who have systemic disease after WBRT for brain metastases. These results should be validated in the future prospective clinical trials.     

Anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma may represent the ultimate dedifferentiation step of thyroid tumorigenesis and is one of the poorest cancers in human. It accounts for less than 2% of thyroid cancers and affects older patients in their sixth to eighth decade. Usual clinical presentation is a rapidly growing thyroid mass invading surrounding structures with compressive symptoms. Cervical lymph nodes enlargement and distant metastases occur frequently. Though cytological results obtained by fine needle aspiration may be suggestive of diagnosis, tissue biopsy for immunohistochemical study can be necessary to exclude lymphoma and to validate aggressive therapies. Patients developing anaplastic thyroid cancer must be referred urgently in cancer centers to plan multimodality therapeutic approach depending on their performance status. The treatment regimen combines surgery when feasible, hyperfractionated and accelerated external beam radiotherapy and doxorubicin based chemotherapy. Such treatment can provide control of locoregional disease but does not impact on overall survival in patients with distant metastases. The prognosis is dismal with a mean survival of four to nine months after diagnosis. Long survivors are patients with emerging disease presenting a resectable tumor and receiving adjuvant radiotherapy and/or chemotherapy. Therapeutic researches investigate redifferenciation strategies and targeted therapies to inhibit EGF receptors and neoplastic angiogenesis. Primary prevention of this lethal disease may consist of adequate treatment of differentiated thyroid cancers and goiters in elderly.     

Epidural spinal cord compression

Spinal cord compression from epidural metastases (epidural spinal cord compression, ESCC) is the most common neurological complication of cancer after brain metastases. Extradural compression represents 97% of spinal cord metastatic lesions. ESCC usually occurs in patients with disseminated disease. The most common tumours associated with ESCC are lung and breast cancers, followed by lymphoma, myeloma, prostate cancer and sarcoma. ESCC represents a medical emergency because delayed treatment can be responsible for irreversible deficits, such as paralysis and loss of sphincter control. Patients with ESCC require a multidisciplinary diagnostic and therapeutic approach. Clinical suspect is radiologically detected for confirmation. The median expected survival time from diagnosis usually ranges from 3 to 6 months. The nature of the primary tumour and the degree of the neurological deficit are the most important factors affecting survival. The lack of prospective randomized trials makes the optimal treatment of ESCC controversial and the decision is to be tailored to the individual. Treatment options include: bed rest, administration of corticosteroids, surgery followed by radiation therapy, radiotherapy alone and, to a limited extent, chemotherapy and hormonal therapy.     

小细胞肺癌治疗中预防性脑照射相关神经毒性的新见解

小细胞肺癌是肺癌中恶性程度相对较高的一种，其颅内的高转移率一直为人们所重视。针对这个情况，预防性脑照射在小细胞肺癌的治疗中已经提出并应用多年。然而，放疗后的多种神经毒性问题一直存在很大争议。近年来，多位学者的观点认为预防性脑照射所带来的神经毒性症状是由多种因素引起，结合预防性脑照射在提高患者生存时间方面的确切疗效，应肯定其在临床应用中的确切价值。     

Hepatic resection for metastatic tumors from noncolorectal carcinoma

BACKGROUND/AIMS: The role of liver resection for hepatic metastases from noncolorectal carcinomas has yet to be clarified. The present study examines a single institutional experience of hepatic resection for noncolorectal metastases. METHODOLOGY: From January 1987 to March 1999, 14 patients underwent curative resection for liver metastases from noncolorectal carcinomas. Records of these patients were reviewed. RESULTS: Resections were performed for liver metastases from gastric cancers (n = 8), pancreatic cancers (n = 2), and cancers of bile duct, the papilla of Vater, kidney, and breast (n = 1, each). Six patients (5 with gastric cancers and 1 with pancreas cancer) presented with synchronous disease and 8 with metachronous disease. In the gastric cancer patients, there are 2 disease-free survivors (26 and 53 months) in the metachronous group, though all of the 5 patients with synchronous disease died within 29 months. All of the 4 patients with pancreatobiliary carcinomas died within 2 years. One case of breast cancer and another of renal cell cancer are alive without disease at 49 and 9 months, respectively. CONCLUSIONS: For metastases from gastric cancers, better survival after hepatic resection is expected in metachronous cases than in synchronous cases. Hepatic resection may afford little benefit for patients with liver metastases from pancretobiliary cancers.     

Extrahepatic metastases occur in a minority of hepatocellular carcinoma patients treated with locoregional therapies: analyzing patterns of progression in 285 patients

Although most cancers are considered predominantly systemic processes, this may not hold true for hepatocellular carcinoma (HCC). The literature regarding patterns of progression of HCC (local versus systemic) has been relatively sparse. Our objectives were to: (1) analyze patterns of progression in HCC patients presenting with intrahepatic disease from initial treatment until death, and (2) identify clinically relevant risk factors for the development of metastases. Over a 9-year period, 285 patients treated with transarterial locoregional therapies underwent scheduled imaging follow-up from treatment until death and were categorized by pattern of progression: (i) intrahepatic (increased tumor enhancement/size, development/progression of vascular invasion, new hepatic lesions) progression or (ii) extrahepatic (adrenal/bone/lung/lymph node) metastases. Uni/multivariate analyses assessing the risk factors for the development of metastases were performed. The median time from last scan to death was 2.4 months (interquartile range: 1.3-4.8 months). The time to development of metastases, vascular invasion, and/or new lesions was 13.8 months (confidence interval: 11.3-17.7 months). Of the 209 patients followed until death, only 50 developed extrahepatic metastases (24%). Multivariate analyses identified age <65 years (P = 0.038), alpha-fetoprotein >200 ng/mL (P = 0.04), and vascular invasion (P = 0.017) as significant predictors of metastases development. CONCLUSION: Knowledge of the risk factors associated with the development of metastases may help guide assessment of patient prognosis. Because 76% of patients presenting with local disease treated with locoregional therapies die without developing extrahepatic metastases, the notion of HCC as a systemic disease, as detected by imaging, may be reconsidered.     

Chemotherapy in breast cancer patients with brain metastases: Have new chemotherapic agents changed the clinical outcome?

Brain metastasis occurs in 15–40% of cancer patients and is present in approximately 10–16% of patients with metastatic breast disease. However, little is known about prognostic factors enabling the early identification of breast cancer patients at risk of CNS metastases. Therapy for brain metastases should be based on several parameters, such as the assessment of prognostic variables, the extent of neurological and systemic disease, and its chemo-sensitivity to previously administered chemotherapy treatments. In view of the known close correlation between metastatic and primary tumor chemosensitivity, the type of chemotherapy chosen should depend more on the tumor histology than on the cerebral distribution of the single drug. More recent drugs with a high impact on the clinical outcome of metastatic breast cancer patients, such as taxanes or trastuzumab, play only a limited role in the treatment of brain metastases.     

The role of systemic chemotherapy in the treatment of brain metastases from small-cell lung cancer

Brain is the most common site of metastatic spread in small-cell lung cancer (SCLC). Approximately 10% of SCLC patients have brain metastases (BM) already at diagnosis and an additional 40% will develop central nervous system (CNS) involvement during their disease course. Although whole brain radiotherapy and corticosteroids is considered the treatment of choice, accumulating evidence suggests that systemic chemotherapy may also play an important role. The concept of the brain as a pharmacologic sanctuary site for established metastases is in contrast with recent clinical observations of frequent BM responses with systemic chemotherapy. During the last decade, several reports about the effect of systemic chemotherapy on BM from SCLC have been published. Pooled data from five studies report 66% response rate (RR) in 64 patients with initial BM. In addition, an average RR of 36% is derived from five studies including 135 patients with delayed BM treated with systemic single agent chemotherapy. Among new drugs with activity in patients with SCLC brain metastases, camptothecin analog topotecan is one of the most promising with a 52% RR. Although whole brain radiation remains the standard treatment of established BM in SCLC there is an emerging role for systemic chemotherapy, particularly with the use of new active drugs as part of combined modality treatments.     

Cerebral metastases of malignant melanoma: contemporary treatment modalities and survival outcome

The aim of our study was to analyze prognostic factors, effect of treatment and survival outcome of a contemporary cohort of melanoma patients with cerebral metastases and eventually propose new recommendations regarding therapy. Sixty four patients with melanoma brain metastases were treated in our department within a 15-year period. We performed a retrospective analysis of their survival with respect to the type of treatment instituted. Four groups were formed according to treatment: Group A patients treated with surgery followed by radiotherapy; group B temozolomide as first-line treatment and radiotherapy after cerebral disease progression; group C radiotherapy alone; group D supportive care only. Patients* characteristics influenced the selection of treatment modality: Group A (7.8%) patients with a single brain metastasis (p=0.001) and controlled extra-cranial disease (p<0.0001), while Group D (21.8%) patients with ulcerated primary lesions (p=0.010) and uncontrolled extra-cranial disease (p<0.0001). Only group B (26.6%) and C (43.7%) patients with similar characteristics including more than one brain lesion. Median overall survival was 3 months. In univariate analysis, median survival for groups A, B, C and D was 12, 5, 3 and 2 months, respectively (p<0.0001). The survival difference between the surgery and non-surgery groups was statistically significant (p=0.0011). Patients treated with supportive care had the worse prognosis (p<0.0001). A survival benefit for patients receiving first-line treatment with temozolomide, as compared to those receiving radiotherapy alone was noted (p=0.0267). In multivariate survival analysis, the number of brain lesions (p=0.0138), the absence of uncontrolled extra-cranial disease (p=0.00221) and the type of treatment for the cerebral disease (p=0.0053) remained significant independent survival predictors. Patients' characteristics remain a critical factor for treatment selection. The number of brain metastases, the extent of disease and the type of treatment represent independent survival predictors. Melanoma patients with a single brain metastasis and controlled extra-cranial disease gain a survival benefit, if surgically treated. Including temozolomide in the first-line treatment of melanoma patients with brain metastases who would have been treated with radiotherapy alone, might present a promising future direction affecting the length of survival.