Pitfalls or promise in prostate cancer immunotherapy-which is winning?

PURPOSE: Immunotherapy with vaccines, cytokines, and monoclonal antibodies against checkpoint molecules has been introduced into the clinical arena. Although all have demonstrated safety in clinical trials in patients with castrate metastatic prostate cancer, no one approach has been able to provide improved overall survival. This article is a review of the current issues and potential resolutions as to how we might go forward in developing and interpreting immunologic trials. DESIGN: Phase I, II, and III trials showed that immunologic tolerance can be abrogated against specific tumor-associated antigens, but the immunologic readouts are suboptimal in determining whether a trial can go forward in its development. RESULTS: Combinatorial approaches appear to be necessary for inducing immunogenicity and antitumor effects. Strategies include irradiated tumor cells lines, costimulatory molecules, or immune checkpoint inhibitors, which are in trials and are under intense scrutiny as to their impact on clinical end points such as time to disease progression and survival. DISCUSSION: Strategies to enhance immunogenicity of vaccines and reassess how to effectively establish interpretable immunologic end points are under development and appear to be successful in affecting how these trials go forward.     

Increasing incidence of oral cancer amongst young persons: what is the aetiology?

The reasons for an increasing incidence of oral cancer, particularly amongst younger persons is unclear. It has been hypothesised either to be a result of an increase in exposure to known risk factors amongst certain groups in the community, or to be due to new aetiological agents. Prior to conducting large expensive population-based studies, it seems appropriate to conduct initial smaller-scale surveys to assess evidence for each of these two hypotheses. This survey of young persons with oral cancer suggest that most are exposed to traditional risk factors of tobacco smoking, drinking alcohol and a low consumption of fruit and vegetables.     

Hypofractioned radiotherapy in prostate cancer: is it the next step?

There are many available options for prostate cancer treatment, including active surveillance, surgery, brachytherapy and external beam radiotherapy. Based on a radiobiological rationale, which considers the prostate tumor as a low α/β tumor, the use of higher and fewer fractions to prostate cancer external beam radiotherapy treatment has been proposed. Instead of the traditional fractions of 1.8–2.0 Gy per day, fractions higher than 2 Gy per day were the subject of a number of studies. In addition, new technologies such as intensity-modulated radiation therapy, image-guided radiation therapy, volumetric-modulated arch therapy and others have emerged as background for changing paradigms. Meanwhile, moderate and ultra-hypofractionation have been the subject of studies in recent years. Some moderate hypofractionation data from randomized controlled trials are ready to use, though other non-inferiority data are still lacking. The data on ultra-hypofractionation are still very new and require further evaluation to determine its long-term safety and efficacy.     

Does age matter in the selection of treatment for men with early-stage prostate cancer?

BACKGROUND: The specific aim of the current study was to compare freedom from biochemical failure, distant metastases-free survival, and overall survival in men age < or = 55 years, men ages 60 to 69 years, and men age > or = 70 years presenting with localized prostate cancer. METHODS: A matched pair analysis compared patients age < or = 55 years (Group 1) who were treated with 3-dimension conformal radiation without androgen deprivation to men age > or = 60 years and < 70 years (Group 2), and men age > or = 70 years (Group 3) who were treated at the Fox Chase Cancer Center between November 1989 and October 2001. The groups were matched for disease stage (T1/T2b vs. T2C/T3), Gleason grade (2-6 vs. 7-10), radiation dose (< 70 Gray [Gy] vs. > or = 70-76 Gy vs. > or = 76 Gy), and pretreatment prostate-specific antigen (PSA) level. Estimates of outcome were accomplished using Kaplan-Meier methodology and compared by age group using the log-rank test. RESULTS: Eighty-four men were identified according to the selection criteria. No statistically significant difference was found in the 5-year overall survival rates for Group 1, Group 2, and Group 3 (94%, 95%, and 87%, respectively) or the 5-year rate of freedom from biochemical failure in Group 1, Group 2, and Group 3 (82%, 76%, and 70%, respectively), or freedom from distant metastases (96%, 97%, and 98%, respectively). CONCLUSIONS: Men age < or = 55 years who present with localized prostate cancer do not appear to have a worse prognosis. External beam radiation therapy appears to be a viable treatment alternative and should be offered to men age < or = 55 years who present with organ-confined prostate cancer.     

Colorectal cancer in young patients: is it a distinct clinical entity?

Background

The incidence of colorectal cancer in young patients is increasing. It remains unclear if the disease has unique features in this age group.

Methods

This was a single-center, retrospective cohort study which included patients diagnosed with colorectal cancer at age ≤40 years in 1997–2013 matched 1:2 by year of diagnosis with consecutive colorectal cancer patients diagnosed at age >50 years during the same period. Patients aged 41–50 years were not included in the study, to accentuate potential age-related differences. Clinicopathological characteristics, treatment, and outcome were compared between groups.

Results

The cohort included 330 patients, followed for a median time of 65.9 months (range 4.7–211). Several significant differences were noted. The younger group had a different ethnic composition. They had higher rates of family history of colorectal cancer (p = 0.003), hereditary colorectal cancer syndromes (p < 0.0001), and inflammatory bowel disease (p = 0.007), and a lower rate of polyps (p < 0.0001). They were more likely to present with stage III or IV disease (p = 0.001), angiolymphatic invasion, signet cell ring adenocarcinoma, and rectal tumors (p = 0.02). Younger patients more frequently received treatment. Young patients had a worse estimated 5-year disease-free survival rate (57.6  vs. 70 %, p = 0.039), but this did not retain significance when analyzed by stage (p = 0.092). Estimated 5-year overall survival rates were 59.1 and 62.1 % in the younger and the control group, respectively (p = 0.565).

Conclusions

Colorectal cancer among young patients may constitute a distinct clinical entity. Further research is needed to validate our findings and define the optimal approach in this population.

     

What is the best test to detect prostate cancer?

The data accumulated during screening of these 300 men suggest that the digital rectal examination is the most efficient test for the diagnosis of prostate cancer. This test is universally available, because physicians believe that it should routinely be performed as part of the physical examination of every man, particularly for men over the age of 40. The digital rectal examination provides useful clinical information about the rectum, anal sphincter, and the quality of stool. Its diagnostic accuracy is unexcelled by more recent, complex, and expensive tests. Finally, in this age of escalating medical costs and physician accountability for these costs, you can't beat the price of the digital rectal examination.     

Androgen deprivation therapy: a survival benefit or detriment in men with high-risk prostate cancer?

Androgen deprivation therapy (ADT) has been used in the management of prostate cancer for more than four decades. Initially, hormone therapy was given largely for palliation of symptomatic metastases. Following several randomized trials of patients with intermediate- to high-risk prostate cancer that demonstrated improvements in biochemical control and survival with the addition of ADT to external beam radiotherapy, there was a dramatic increase in the use of hormone therapy in the definitive setting. More recently, the safety of ADT has been questioned, as some studies have suggested an association of hormone therapy with increased cardiovascular morbidity and mortality. This is particularly worrisome in light of practice patterns that show ADT use extrapolated to situations for which there has been no proven benefit. In the setting of dose escalation with modern radiotherapy, in conjunction with the latest concerns about cardiovascular morbidity with ADT, the magnitude of expected benefit along with potential risks of ADT use must be carefully considered for each patient.     

Androgen receptor expression in prostate cancer stem cells: is there a conundrum?

Androgen deprivation therapy (ADT) is standard frontline therapy for metastatic prostate cancer. However, prostate cancer progresses to a castrate-resistant state. The response of prostate cancer to androgen deprivation is mediated by the androgen receptor (AR). Castrate-resistant disease is marked by a gain-of-function in AR and AR reactivation. The stem cell hypothesis of cancer would therefore predict that AR should be expressed in the prostate cancer stem cell, since genetic selection for gain-of-function changes in AR, such as AR gene amplification, should occur at the level of the stem cell population. Initial reports characterizing prostate cancer stem cells suggest that AR is not expressed in this population, which is an apparent conundrum. Here, we examined the CD44+/24- LNCaP putative stem cell population by in-cell Western and show that AR is expressed at the protein level. Our findings suggest that at least a subset of prostate cancers express AR in the putative stem cell population.     

Salvage laparoscopic surgery in advanced prostate cancer: is it possible or beneficial?

Purpose: The surgical management of recurrent urological cancer continues to evolve. This review focuses on the role laparoscopic surgical techniques have within recurrent prostate treatments. Methods: A literature search from 1990 to 2007 was conducted using the PubMed database to determine the role of laparoscopic salvage surgery for prostate cancers. In all articles studied, we evaluated: estimated blood loss; transfusion rates; hemoglobin level; serum and drain fluid creatinine levels; bowel injury; hospital stay and complication rates. Results: Laparoscopic surgery is used regularly for the treatment of urological cancers; however, its role in treating radiorecurrent or chemoradiorecurrent cancer is unknown. Adjuvant chemo-radiotherapy, other experimental localized therapies (cryotherapy) or hormonal therapy are known to affect the operative field, causing greater morbidity in open surgery. Relative survival rates were lowest among patients who received no treatment and highest among patients who underwent surgical procedures. Conclusions: Although associated with significant morbidity, salvage prostatectomy remains a viable form of therapy. Laparoscopic salvage radical prostatectomy for recurrent cancer is feasible with no more morbidity than an open procedure, with promising short-term oncologic and functional outcomes. Long-term data will ultimately confirm the viability of the laparoscopic approach most probably in a multicenter setting.