Search

Ankur R Parikh,1 Siraj M Ali,2 Alexa B Schrock,2 Lee A Albacker,2 Vincent A Miller,2 Phil J Stephens,2 Pamela Crilley,1 Maurie Markman1 1Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, PA, USA; 2Foundation Medicine, Inc, Cambridge, MA, USA Abstract: In non-small-cell lung cancer (NSCLC) refractory to standard therapy and which lacks well-known oncogenic drivers, genomic profiling can still identify genomic alterations that may suggest potential sensitivity to targeted therapy. PTEN mutation in NSCLC may be sensitizing to analogs of rapamycin such as everolimus or temsirolimus, but more investigation is needed. We report the case of a patient with metastatic NSCLC harboring a PTEN mutation as well as high tumor mutational burden and PD-L1 positivity with a durable response to temsirolimus, but refractory to a checkpoint inhibitor. Even in the event of failure of treatment with checkpoint inhibitors in the background of a case with a higher tumor mutational burden and PD-L1 positivity, targeting specific genomic alterations may still result in patient benefit. Keywords: genomic profiling, temsirolimus, targeted therapy, immunotherapy

Digant Gupta, Maurie Markman, Mark Rodeghier, Christopher G LisCancer Treatment Centers of America®, Schaumburg, IL, USAPurpose: Despite the recognized relevance of symptom burden in pancreatic cancer, there has been limited exploration of whether an individual patient's satisfaction with the overall quality of care received might influence outcome. We evaluated the relationship between patient satisfaction with health service quality and survival in patients with pancreatic cancer.Patients and methods: A random sample of 496 pancreatic cancer patients treated at Cancer Treatment Centers of America® (CTCA) between July 2007 and December 2010. A questionnaire that covered several dimensions of patient satisfaction was administered. Items were measured on a seven-point Likert scale ranging from “completely dissatisfied” to “completely satisfied.” Patient survival was the primary end point. Cox regression was used to evaluate the association between patient satisfaction and survival.Results: The response rate for this study was 72%. Of the 496 patients, 345 (69.6%) reported being “completely satisfied” with the care provided. Median overall survival was 7.9 months. On univariate analysis, patients reporting they were “completely satisfied” experienced superior survival compared with patients stating they were “not completely satisfied” (hazard ratio = 0.62; 95% confidence interval: 0.50–0.77; P < 0.001). On multivariate analysis controlling for stage at diagnosis, treatment history, and specific CTCA treatment center, “completely satisfied” patients demonstrated significantly lower mortality (hazard ratio = 0.63; 95% confidence interval: 0.51–0.79; P < 0.001).Conclusion: In this exploratory analysis, patient satisfaction with health service quality was an independent predictor of survival in pancreatic cancer. Further exploration of a possible meaningful relationship between patient satisfaction with the care they have received and outcome in this difficult malignancy is indicated.Keywords: health services, oncology, prognosis, survival

Maurie MarkmanCancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, PA, USAAbstract: Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. The drug is frequently employed as a single agent in the platinum-resistant setting, and recently reported data reveal the superiority of the combination of PLD plus carboplatin, compared with the platinum drug plus paclitaxel, in delaying the time to disease progression in women with recurrent (potentially platinum-sensitive) disease. Current research efforts involving PLD in ovarian cancer are focusing on adding novel targeted drugs to this cytotoxic agent. The utility of such approaches in the platinum-resistant population, compared with the sequential administration of single agents active in this setting, remains to be determined.Keywords: PLD, carboplatin, paclitaxel, platinum-sensitive, platinum-resistant

This article reviews intravenous vitamin C (IV C) in cancer care and offers a rational approach to enable medical oncologists and integrative practitioners to safely provide IV C combined with oral vitamin C to patients. The use of IV C is a safe supportive intervention to decrease inf lammation in the patient and to improve symptoms related to antioxidant deficiency, disease processes, and side effects of standard cancer treatments. A proposed rationale, together with relevant clinical safety considerations for the application of IV C in oncologic supportive care, is provided. [ABSTRACT FROM AUTHOR]

Objectives: Synergism between gemcitabine and platinum is known clinically. Bevacizumab in combination with single-agent chemotherapy has demonstrated significant clinical activity in platinum-resistant recurrent ovarian cancer in AURELIA study. However, the efficacy of platinum-gemcitabine-bevacizumab (PGA) has not been investigated in the platinum-resistant population. Materials and Methods: A retrospective chart review was conducted in all patients with platinum-resistant/refractory ovarian cancer treated with triplet combination therapy containing a platinum agent, gemcitabine, and bevacizumab between July 2011 and December 2013. Results: In total, 13 patients met the selection criteria, including ten patients with resistant disease (10/13, 77%) and three patients with refractory disease (3/13, 23%). Most of the patients were heavily pre-treated, having received over three lines of prior chemotherapy regimens on average (range 1-11). All patients had previously received taxane therapy; four patients received gemcitabine, seven patients failed combination regimens including bevacizumab, and three patients progressed on chemotherapy including both gemcitabine and bevacizumab. Ten patients responded biochemically to the therapy (defined by CA-125 declined by at least 50%). Of ten responders, one patient achieved CR for 24 months (8%), six patients achieved PR for 6.8 months (46%), three had stable disease for 6.7 months (23%), and three patients had PD (23%) by RECIST 1.1 criteria. The regimen was well-tolerated. One patient (8%) developed grade 3 neutropenia and neutropenic fever, requiring hospitalization, two patients developed grade 3 thrombocytopenia, two patients (15%) developed thrombosis in internal jugular vein, requiring discontinuation of bevacizumab, one patient (8%) experienced skin ulcer, and two patients developed thrombosis in internal jugular vein, requiring discontinuation of bevacizumab. Conclusions: Combination of PGA appears to be safe and very active against platinum-resistant/refractory ovarian cancer and merits further evaluation prospectively. A randomized phase II study (NCT01936974) is currently under way to confirm this important finding. [ABSTRACT FROM AUTHOR]

The article looks at the efficacy of chemotherapy in treating epithelial ovarian cancer. The cancer has been known to be treated using existing medications including cisplatin, carboplatin, and paclitaxel, although the former drug became a treatment standard for cytotoxic chemotherapy. Oncologists have also tested platinum-based chemotherapy on its potential as an alternative ovarian cancer treatment, where cisplatin-cyclophosphamide regimen is a known drug mix used in a daily cancer treatment practice.

Background: The objective of the current study was to determine the prognostic significance of a pretreatment serum CA 125 level in patients with advanced epithelial ovarian carcinoma (EOC) who received treatment with a standard chemotherapy regimen.Methods: Patients with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma who were on 1 of 7 Gynecologic Oncology Group (GOG) phase 3 trials and received treatment with a standard regimen of intravenous cisplatin and paclitaxel were included. A Cox regression model was used to assess the impact of CA 125 levels drawn before the initiation of chemotherapy on progression-free survival (PFS) both overall and by subgroup, including surgical debulking status, disease stage, and histologic subtype.Results: In total, 1,299 patients who were on the cisplatin/paclitaxel arms of the GOG trials were eligible. The median CA 125 level was 246 U/mL. Only 7.6% of patients had a normal CA 125 level (Conclusions: A normal CA 125 level in the setting of advanced EOC was rare even after surgical debulking. The pretreatment CA 125 level was an independent predictor of PFS in patients with advanced EOC who received a standard chemotherapy regimen, particularly in the setting of disease that was debulked to a microscopic residual and in the serous or endometrioid subtypes. [ABSTRACT FROM AUTHOR]

Despite the conduct of numerous randomized clinical trials in advanced ovarian cancer over the past decade, no new primary chemotherapeuric regimen has demonstrated a major improvement in overall survival (OS) compared with a program of a platinum agent plus a taxane. This suggests that a plateau in the effectiveness of cytotoxic chemotherapy regimens has been reached and that novel treatment paradigms are necessary. One approach is the use of maintenance therapy after an initial response to standard regimens has heen achieved. This possibility is being exploted with a number of targeted therapeutic strategies that focus on theorized unique molecular differences between tumors and normal tissue. By inhibiting or delaying tumor growth or spread, such agents delivered as maintenance therapy might extend the time to disease progression but might not necessarily be associated with improvements in objective response based on tumor shrinkage. Furthermore, these highly clinically relevant outcomes might not always be detectable in short-term trials oriented toward measurable tumor response, and longer treatment periods might be necessary to allow time for the identification of responder subsets or development of an immune response. Even defining the optimal regimen to undergo definitive testing could be problematic. As a result, innovative trial designs might be required to both detect potentially meaningful biologic activity and to identify patient subsets most likely to respond to trearment before largescale phase III trials are performed. [ABSTRACT FROM AUTHOR]

Although ovarian cancer is highly sensitive to chemotherapy, the majority of patients experience recurrence. As a result, it is rational to consider a maintenance strategy to improve overall survival (even if it does not increase the rate of 'cure') and delay the time to symptomatic disease progression. Although a phase III trial of single-agent paclitaxel delivered on a monthly schedule for 12 cycles after the attainment of a clinically defined complete response to primary chemotherapy revealed a substantial improvement in progression-free survival, the effect of this strategy on overall survival remains unresolved. Hopefully, the role of maintenance therapy in patients with ovarian cancer will be defined by ongoing and future trials. [ABSTRACT FROM AUTHOR]

Primary debulking surgery by a gynecologic oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumor load. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in stage IIIC and IV patients. Interval debulking is defined as an operation performed after a short course of induction chemotherapy. Based on the randomized European Organization for Research and Treatment of Cancer--Gynecological Cancer Group (EORTC-GCG) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on Gynecologic Oncology Group (GOG) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery. [ABSTRACT FROM AUTHOR]

The use of intraperitoneal drug delivery in the treatment of malignant disease confined to the peritoneal cavity is based on the theoretical potential for increased exposure of the tumour to antineoplastic agents leading to improved cytotoxicity. Phase I studies have explored the safety and pharmacokinetic advantage of the regional administration of several drugs, including cisplatin (10 times higher than systemic delivery) and paclitaxel (1000 times higher). Phase II trials of second-line intraperitoneal chemotherapy of ovarian cancer, generally with cisplatin, have shown the potential for patients to achieve surgically-documented complete responses. Randomised trials of second-line regional therapy in patients with ovarian cancer have yet to be conducted, although non-randomised single institution experience has suggested the potential for long-term disease-free survival with this strategy. By contrast, several well-planned randomised trials of first-line intraperitoneal chemotherapy of small-volume residual advanced ovarian cancer after primary surgical cytoreduction have reported a survival advantage with regional drug delivery. Although a rationale can be proposed for intraperitoneal antineoplastic drug delivery in non-ovarian malignant disease involving the peritoneal cavity, current data do not support the use of this strategy outside the confines of well-designed clinical trials. [ABSTRACT FROM AUTHOR]

No clinical guidelines advocate screening. Although monitoring women at high risk with transvaginal sonography and serum CA-125 testing may be reasonable, poor specificity and sensitivity of these tools is disheartening. [ABSTRACT FROM AUTHOR]

Acute hypersensitivity reactions (HSRs) are an unpredictable and potentially catastrophic complication of treatment with chemotherapeutic agents. Reactions may affect any organ system in the body and range widely in severity from mild pruritus to systemic anaphylaxis. Certain classes of chemotherapeutic agents, such as the taxanes, platinum compounds, asparaginases, and epipodophyllotoxins are commonly associated with HSRs. The clinical characteristics of these high risk agents with respect to HSRs are discussed in this review. Protocols to prevent or reduce the severity of these reactions have been developed, but despite these attempts, HSRs will still happen. Should a reaction occur, it is imperative that it be recognised quickly in order to minimise exposure to the inciting agent and implement appropriate therapeutic and supportive measures. When a patient becomes sensitised to a chemotherapeutic agent, avoidance of re-exposure is the mainstay of future prevention. For sensitised patients who have derived clinically meaningful benefit from a particular agent, however, continuation of treatment with the agent is desirable. Options may include attempting a trial of desensitisation or treatment with a related compound. Virtually all patients demonstrating HSRs to paclitaxel and docetaxel are able to successfully tolerate re-treatment following discontinuation and administration of diphenhydramine and hydrocortisone. Re-treatment has generally been less successful with platinum compounds, with recurrent HSRs occurring in up to 50% of patients following desensitisation protocols. Patients sensitised to asparaginase are often able to tolerate the alternative preparations, Erwinia carotovora asparaginase or polyethylene glycol-modified Escherichia coli asparaginase. There is very little experience with re-treatment following sensitisation to the epipodophyllotoxins. As re-treatment may have serious consequences, careful consideration of the risks and benefits of these strategies is imperative when deciding among these options. [ABSTRACT FROM AUTHOR]

Objective: Our goal was to provide health-care providers, patients, and the general public with an assessment of currently available data regarding the use of adjuvant therapy for breast cancer.Participants: The participants included a non-Federal, non-advocate, 14-member panel representing the fields of oncology, radiology, surgery, pathology, statistics, public health, and health policy as well as patient representatives. In addition, 30 experts in medical oncology, radiation oncology, biostatistics, epidemiology, surgical oncology, and clinical trials presented data to the panel and to a conference audience of 1000.Evidence: The literature was searched with the use of MEDLINE(TM) for January 1995 through July 2000, and an extensive bibliography of 2230 references was provided to the panel. Experts prepared abstracts for their conference presentations with relevant citations from the literature. Evidence from randomized clinical trials and evidence from prospective studies were given precedence over clinical anecdotal experience.Consensus Process: The panel, answering predefined questions, developed its conclusions based on the evidence presented in open forum and the scientific literature. The panel composed a draft statement, which was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately after its release at the conference and was updated with the panel's final revisions. The statement is available at http://consensus.nih.gov.Conclusions: The panel concludes that decisions regarding adjuvant hormonal therapy should be based on the presence of hormone receptor protein in tumor tissues. Adjuvant hormonal therapy should be offered only to women whose tumors express hormone receptor protein. Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status. The inclusion of anthracyclines in adjuvant chemotherapy regimens produces a small but statistically significant improvement in survival over non-anthracycline-containing regimens. Available data are currently inconclusive regarding the use of taxanes in adjuvant treatment of lymph node-positive breast cancer. The use of adjuvant dose-intensive chemotherapy regimens in high-risk breast cancer and of taxanes in lymph node-negative breast cancer should be restricted to randomized trials. Ongoing studies evaluating these treatment strategies should be supported to determine if such strategies have a role in adjuvant treatment. Studies to date have included few patients older than 70 years. There is a critical need for trials to evaluate the role of adjuvant chemotherapy in these women. There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary cancer. Currently, the role of postmastectomy radiotherapy for patients with one to three positive lymph nodes remains uncertain and should be tested in a randomized controlled trial. Individual patients differ in the importance they place on the risks and benefits of adjuvant treatments. Quality of life needs to be evaluated in selected randomized clinical trials to examine the impact of the major acute and long-term side effects of adjuvant treatments, particularly premature menopause, weight gain, mild memory loss, and fatigue. Methods to support shared decision-making between patients and their physicians have been successful in trials; they need to be tailored for diverse populations and should be tested for broader dissemination. [ABSTRACT FROM AUTHOR]

The administration of antineoplastic agents directly into the peritoneal cavity as treatment of localised cancer is based on sound pharmacokinetic principles. This unique technique has to the potential to optimise outcome in settings where preclinical and clinical data suggest that cytotoxicity of a specific drug against a particular tumour type is enhanced by either increasing the drug concentration or duration of exposure. Phase I trials have confirmed the safety and pharmacokinetic advantage for a number of agents delivered by the intraperitoneal relative to the systemic route, including cisplatin (10- to 20-fold advantage for regional delivery), carboplatin (10- to 20-fold advantage), and paclitaxel (1000-fold advantage). In phase II trials, performed mostly in patients with ovarian cancer, this approach has achieved objective responses in settings where intravenous drug delivery has not achieved the desired effect (e.g. surgically documented complete response using intraperitoneal cisplatin as second-line therapy of ovarian cancer). Phase III trials employing intraperitoneal cisplatin as initial treatment of small volume advanced ovarian cancer have demonstrated that regional therapy results in a modest, but statistically significant, improvement in both progression-free and overall survival compared to intravenous cisplatin. Further exploration of this novel method of treatment, including the conduct of definitive randomised phase III clinical trials, is indicated in ovarian cancer and in other tumour types where clinical manifestations are principally localised to the peritoneal cavity. [ABSTRACT FROM AUTHOR]

Some side effects of chemotherapy are preventable, while other can be minimized if tended to promptly. This review covers the spectrum to toxic events and offers practical guidance on managing them. [ABSTRACT FROM AUTHOR]

At what point should curative cancer therapy stop and palliative care begin? What constitutes adequate palliation? Here are some up-to-date, authoritative solutions to these thorny questions. [ABSTRACT FROM AUTHOR]

A patient with Waldenström's macroglobulinaemia presented with visual reduction in both eyes. The funduscopic and angiographic demonstrations of venous engorgement ('string of sausages'), retinal haemorrhages at all levels, retinal and disc oedema, and serous detachment of the maculas were consistent with this diagnosis. The cryoprecipitation of the immunoglobulin at a temperature slightly below body temperature precluded routine blood studies and plasmapheresis. Plasmapheresis was ultimately performed without difficulty with the patient and equipment at 88 degrees F (31 degrees C). Despite marked improvement in the funduscopic and angiographic appearance of the retina, perifoveal capillary nonperfusion and serous elevation of the macula persisted. Even when the maculas flattened in both eyes, no visual recovery occurred. Early diagnosis, even on a clinical basis when laboratory studies cannot be performed, and early plasmapheresis to reduce serum viscosity are warranted to prevent intravascular occlusion in the perifoveal capillary bed, deposition of immunoglobulin in the retina, and transudation in the subretinal space. [ABSTRACT FROM PUBLISHER]

A total of 21 patients with advanced soft tissue sarcoma enrolled in a phase II trial of 3.5 g/m2 N-phosphonacetyl-L-aspartate (PALA) given intravenously every 3 weeks plus 50 mg/m2 dipyridamole (Persantine) given orally every 6 h. Dipyridamole administration was initiated 1 week before the first dose of PALA. Peak and trough plasma concentrations of dipyridamole were measured before and after the first dose of PALA in 14 patients. In all, 19 patients were evaluable for therapeutic response. One subject experienced partial regression of a pulmonary metastasis; no other major response was observed. Diarrhea was the most prominent toxicity; in one patient it was life-threatening and was associated with a severe rash. On the day preceding PALA administration, the median peak plasma concentration of dipyridamole was 2,208 ng/ml and the median trough value was 904 ng/ml. Similar values were obtained on the day of PALA administration. Although the levels achieved were similar to those required to modulate the activity of PALA in preclinical systems, the therapeutic results obtained in the present study were not superior to those reported for PALA alone in previously treated patients with soft-tissue sarcoma. [ABSTRACT FROM AUTHOR]

The availability of uridine can alter the sensitivity of tumor cells to antimetabolites such as N-phosphonacetyl-L-aspartic acid (PALA) and acivicin by virtue of the cell's ability to salvage preformed metabolites from its environment. We investigated the pharmacokinetics of physiologically relevant amounts of uridine in cancer patients in a pilot study to further our understanding of uridine metabolism in the human body. Four cancer patients, two males and two females, were given an i.v. bolus of a trace amount of radiolabeled uridine. The nucleoside disappeared from the plasma in a triphasic manner, with initial half-lives of 0.57 +/- 0.28 and 1.79 +/- 0.62 min and a terminal half-life of 17.5 +/- 7.3 min. The volume of distribution was 481 +/- 70 ml/kg, and the plasma uridine clearance was calculated to be 1.70 +/- 0.42 l/min. Simultaneous plasma and bone marrow uridine concentrations were measured in a separate group of seven healthy volunteers. The uridine concentration in plasma was 2.32 +/- 0.58 microM, and that in the bone marrow plasma was 10.44 +/- 5.06 microM. These results suggest a very rapid turnover of uridine in the plasma when the nucleoside is present at physiologic concentrations, and that there is a locally high concentration of uridine available for salvage in the bone marrow. [ABSTRACT FROM AUTHOR]

While N-phosphonacetyl-L-aspartic acid (PALA), an inhibitor of de novo pyrimidine biosynthesis, demonstrated a unique spectrum of activity during preclinical drug evaluation, multiple clinical trials have shown it to possess minimal clinical activity. One explanation for the disappointing results is the possibility that tumor cells are able to utilize circulating uridine in the synthesis of pyrimidines (salvage pathway). Dipyridamole, an inhibitor of nucleoside transport, has been demonstrated experimentally to potentiate the cytotoxicity of PALA significantly. In addition, this agent has a long safety record when used clinically in man. A phase I trial of this two-drug combination was therefore conducted, with a fixed oral dose of dipyridamole (50 mg/m2 every 6 h) and an escalating i.v. dose of PALA administered every 3 weeks. The dose-limiting toxicity with this schedule was diarrhea and abdominal cramping pain at a PALA dose of 3900-4200 mg/m2. Among the 65 patients participating in this trial 4 objective responses (2 partial, 2 minimal) were observed. Because of the potential for unique clinical synergy between PALA and dipyridamole further investigation should be considered. [ABSTRACT FROM AUTHOR]

Context: Lysophosphatidic acid (LPA) has been shown to stimulate proliferation of ovarian cancer cells and is present in the ascitic fluid of patients with ovarian cancer.Objectives: To determine whether elevated levels of LPA are present in plasma from patients with ovarian cancer and other gynecologic malignancies compared with healthy controls and to evaluate whether an elevated LPA plasma level may be a biomarker for these diseases.Design: A research assay was used to measure total LPA levels in plasma from healthy women and women with different diseases. All LPA assays and comparison of LPA levels and CA125 (an ovarian cancer biomarker) levels were performed by observers blinded to patient status or group.Setting: The Cleveland Clinic Foundation.Participants: A convenience sample of 48 healthy control women, 48 women with ovarian cancer, 36 women with other gynecologic cancers, 17 women with benign gynecologic diseases, 11 women with breast cancer, and 5 women with leukemias.Main Outcome Measures: Total LPA levels in plasma samples from patients and controls.Results: Patients in the ovarian cancer group had significantly higher plasma LPA levels (mean, 8.6 micromol/L; range, 1.0-43.1 micromol/L) compared with the healthy control group (mean, 0.6 micromol/L; range, <0.1-6.3 micromol/L) (P<.001). Elevated plasma LPA levels were detected in 9 of 10 patients with stage I ovarian cancer, 24 of 24 patients with stage II, III, and IV ovarian cancer, and 14 of 14 patients with recurrent ovarian cancer. Of 36 patients with other gynecologic cancers, 33 also showed higher LPA levels(mean, 14.9 micromol/L; range, <0.1-63.2 pmol/L), compared with healthy controls (P<.001). Elevated plasma LPA levels were detected in 5 of 48 controls and 4 of 17 patients with benign gynecologic diseases and in no women with breast cancer or leukemia. In comparison, among a subset of patients with ovarian cancer, 28 of 47 had elevated CA125 levels, including 2 of 9 patients with stage I disease.Conclusions: Plasma LPA levels may represent a potential biomarker for ovarian cancer and other gynecologic cancers. However, these findings are preliminary and require confirmation in larger studies. [ABSTRACT FROM AUTHOR]