Julio Hajdenberg

Lifestyle Interventions in the Prevention and Treatment of Cancer

Despite evidence that cancer death rates in the United States are declining, the absolute number of new cancers and cancer deaths continues to increase, and there is clear evidence that certain human behaviors are influencing these increases. The 4 major factors of lifestyle that continue to be causally related to certain cancers—tobacco use, an unhealthy diet, inadequate exercise, and excessive exposure to ultraviolet radiation—are each independently important in their effects on the genetic and molecular processes that result in the malignant transformation of human cells. There is both irrefutable and otherwise strong evidence that 4 common cancers that occur in the United States—lung cancer, colon/rectal cancer, breast cancer, and prostate cancer—and a less common cancer, malignant melanoma, have etiologic factors that are lifestyle based and therefore controllable through alterations in human behavior. These cancers and the evidence that lifestyle is important in the causation and/or prevention of the disease are the subjects of this review.

Locally advanced paraganglioma of the urinary bladder: a case report

BackgroundParaganglioma of the urinary bladder is a rare tumor. Herein we sought to describe a case of locally advanced paraganglioma of the urinary bladder managed by partial cystectomy and extended pelvic lymph node dissection.Case presentationThe case of a 43-year old Haitian male with locally advanced paraganglioma of the urinary bladder is presented in detail. Through surgical extirpation, our patient was rendered disease-free. Eighteen months later the patient is doing well without symptoms but is noted to have subcentimeter bilateral pulmonary nodules and retroperitoneal lymph nodes. No further therapy has been initiated at this time.ConclusionsPatients with localized tumors have an extremely favorable prognosis and may be managed by less aggressive modalities, whereas patients with metastatic disease have a significant reduced survival rate despite aggressive treatment.

Continuous androgen-deprivation therapy increased risk for diabetes and fragility fractures in older men with prostate cancer

Question Is continuous androgen-deprivation therapy (ADT) associated with diabetes mellitus, myocardial infarction, cardiovascular mortality, or fragility fractures in older men with prostate cancer? Methods Design Cohort study with linkage of administrative databases; mean follow-up was 6.5 years. Setting Ontario, Canada. Patients 38158 men 66 years of age (mean age 75 y) with prostate cancer were identified from the Ontario Cancer Registry. ADT users (n =19079) had received medical ADT (luteinizing hormonereleasing hormone agonists, nonsteroidal antiandrogens, and/or steroidal antiandrogens) continuously for 6 months or had bilateral orchiectomy. Non-ADT users (n =19079) had not received ADT after prostate cancer diagnosis and were matched with ADT users on age at diagnosis, prior radical prostatectomy, and on a propensity score based on age at time of study, year of diagnosis, comorbidity, medication use, and socioeconomic factors. Risk factor ADT use. Outcomes Development of myocardial infarction, sudden cardiac death, and diabetes (30 d after starting ADT). Secondary outcomes included fragility fractures. Main result Men who used ADT were at greater risk for diabetes and fragility fractures but not myocardial infarction or sudden cardiac death (Table). Conclusion Continuous ADT use was associated with increased risk for diabetes and fragility fractures but not myocardial infarction or sudden cardiac death in older men with prostate cancer. Associations between androgen-deprivation therapy (ADT) and adverse outcomes in older men with prostate cancer* Outcomes At a mean 6.5 y ADT use No ADT use Adjusted hazard ratio (95% CI) Myocardial infarction 4.8% 5.5% 0.92 (0.84 to 1.00) Sudden cardiac death 2.0% 2.2% 0.96 (0.83 to 1.10) Diabetes 7.1% 6.0% 1.24 (1.15 to 1.35) Fragility fracture 9.0% 5.9% 1.65 (1.53 to 1.78) *CI defined in Glossary. Adjusted for income quintile and rurality. Not statistically significant. Commentary Over the past 3 years, studies (mostly observational) have had conflicting findings on the risk for adverse cardiovascular (CV) events associated with ADT in older men (1, 2). The study by Alibhai and colleagues, the largest to date, linked the Ontario Cancer Registry with other provincial databases to determine the association between ADT and diabetes mellitus, CV mortality, and other outcomes in older men with prostate cancer. Propensity matching was used to decrease the inherent bias of an observational design. The study found an increased risk for incident diabetes mellitus but not sudden death, MI, or other secondary CV outcomes. The authors suggest that the duration of follow-up may have been too short to detect any increases in CV morbidity associated with an increase in diabetes mellitus. Potential methodological problems related to the study design, such as undercoding or more intense care and scrutiny of ADT-treated patients, are probably unavoidable. Nanda and colleagues (3) assessed the risk for all-cause mortality in neoadjuvant ADT users and found an increased risk in patients with a history of myocardial infarction or congestive heart failure, but not overall. Alibhai and colleagues did not assess overall mortality, but they found no evidence of increased risk for MI or sudden cardiac death in ADT users, even after accounting for history of MI, congestive cardiac failure, and other risk factors. Alibhai and colleagues provide additional evidence of the long-term toxicities of ADT. This evidence complements the National Comprehensive Cancer Network guidelines (4), which recommend ADT only for situations in which a survival benefit has been clearly shownnamely, for patients with established metastatic disease, and for selected patients having surgery or radiation for local or locoregional disease with a high likelihood of recurrence.

ACP Journal Club. In high-risk patients, oral nicotinamide reduced number of new nonmelanoma skin cancers during treatment.

Question In high-risk patients, does oral nicotinamide reduce number of nonmelanoma skin cancers compared with placebo? Methods Design Randomized placebo-controlled trial (Oral Nicotinamide to Reduce Actinic Cancer [ONTRAC] trial). Australian New Zealand Clinical Trials Registry ACTRN12612000625875. Allocation Concealed.* Blinding Blinded* (patients, clinicians, and outcome assessors). Follow-up period 12 months (treatment period) and 18 months (6 months after treatment). Setting 2 hospitals in Sydney, Australia. Patients 386 patients 18 years of age (mean age 66 y, 63% men, mean number of actinic keratoses 46 to 48) who had 2 nonmelanoma skin cancers confirmed by histology in the past 5 years. Exclusion criteria included pregnancy or breast-feeding; immunosuppression; reduced liver or kidney function; active peptic ulcer disease; hypotension; recent myocardial infarction; genetic skin cancer syndrome; confluent skin cancer; use of nicotinamide supplements, oral retinoids, or field treatment for actinic keratosis in the past 4 weeks; or metastatic cancer, invasive melanoma, or internal cancer in the past 5 years. Intervention Oral nicotinamide, 500 mg twice/d (n =193), or placebo (n =193) for 12 months. Outcomes Primary outcome was number of new nonmelanoma skin cancers (basal cell or squamous cell carcinomas) confirmed by histology up to 12 months. Other outcomes included number of new basal cell carcinomas, new squamous cell carcinomas, and actinic keratoses up to 12 months; number of new nonmelanoma skin cancers at 12 to 18 months; and adverse events. Patient follow-up 96% at 12 months and {95% at 18 months} (intention-to-treat analysis). Main results Nicotinamide reduced number of new nonmelanoma skin cancers (Table) and number of actinic keratoses {adjusted mean change from baseline 6.9 vs 3.9, P =0.001} compared with placebo at 12 months. Groups did not differ for number of new basal cell or squamous cell carcinomas at 12 months (Table) or new nonmelanoma skin cancers in the 6-month posttreatment period (mean 0.8 vs 0.8 lesions/person, P =0.33). 67 serious adverse events occurred in the nicotinamide group and 65 in the placebo group over 12 months. Conclusion In patients with 2 previous nonmelanoma skin cancers, oral nicotinamide reduced the number of new nonmelanoma skin cancers per person during 12 months of treatment. Nicotinamide vs placebo in patients with 2 nonmelanoma skin cancers in the past 5 y Outcomes Mean lesions/person At 12 months Nicotinamide Placebo Relative rate reduction (95% CI) New nonmelanoma skin cancers 1.8 2.4 23% (4 to 38) New basal cell carcinomas 1.3 1.7 20% (6 to 39) New squamous cell carcinomas 0.5 0.7 30% (0 to 51) CI defined in Glossary. Adjusted for center and 5-year history of nonmelanoma skin cancer. Commentary The trial by Chen and colleagues followed patients for 12 months during therapy and 6 months off therapy, focusing on a very high-risk subset of a population in which about 2 in 3 persons may be expected to develop skin cancer by 70 years of age (1). The results are consistent with previous preclinical and clinical studies in similar risk groups by the same investigators (2) and should be generalizable to other populations in which risk for ultraviolet (UV)-induced skin damage is high. However, patients who were immunosuppressed, a group at high risk for UV-induced nonmelanoma skin cancer, were excluded. Benefits of nicotinamide were seen for all nonmelanoma skin cancers, basal cell carcinoma, squamous cell carcinoma, and actinic keratosis, and dissipated when nicotinamide was stopped. This is consistent with the proposed mechanism of action of the drug on extensively sun-damaged skin, where DNA repair mechanisms and cutaneous immunity seem to be needed continuously as cells renew. The trial also found that compliance with oral nicotinamide was high (about 90%), whereas compliance with sunscreen was about 50%. The results of the trial provide a solid rationale for the use of nicotinamide as a secondary preventive agent. Given its low toxicity and cost (3), clinicians may be tempted to use the drug as a primary preventive agent in related populations at risk (e.g., those without previous nonmelanoma skin cancer but with extensive solar damage, actinic keratoses, or long-term immunosuppression) in the absence of direct level 1 evidence. However, until additional data are available, physicians should inform patients that the benefits and risks of long-term exposure to nicotinamide are unknown (4). They must continue to reinforce the need for sunscreen, which is useful for preventing melanoma, a potentially lethal condition that is not treated with nicotinamide.

Radical prostatectomy reduced long-term mortality more than watchful waiting in early prostate cancer

Question In early prostate cancer, how do radical prostatectomy (RP) and watchful waiting (WW) compare for long-term mortality? Methods Design Randomized controlled trial (RCT) (Scandinavian Prostate Cancer Group Study Number 4 [SPCG-4]). Allocation Unclear allocation concealment.* Blinding Blinded* (cause of death adjudicators). Follow-up period Median 13 years. Setting 14 centers in Sweden, Finland, and Iceland. Patients 698 men <75 years of age (mean age 65 y, mean prostate-specific antigen [PSA] level 13 ng/mL) who had well-differentiated to moderately welldifferentiated, localized prostate cancer (stages T0d, T1, T1b, T1c, or T2); serum PSA level <50 ng/mL; and a negative bone scan. Exclusion criteria included life expectancy 10 years or other cancers. Intervention RP (n =349) or WW (n =349). Outcomes Mortality, prostate cancer mortality, and distant metastases. Secondary outcomes included initiation of androgen deprivation therapy. Patient follow-up >99.5%. Main results RP reduced risk for all-cause mortality, prostate cancer mortality, distant metastases, and use of androgen deprivation therapy more than WW (Table). Conclusion In early prostate cancer, radical prostatectomy reduced risk for long-term mortality more than watchful waiting. Radical prostatectomy (RP) vs watchful waiting (WW) in early prostate cancer Outcomes RP WW At a median 13 y RRR (95% CI) NNT (CI) All-cause mortality 56% 69% 29% (14 to 41) 6 (4 to 11) Prostate cancer mortality 18% 29% 44% (23 to 59) 8 (6 to 16) Distant metastases 26% 38% 43% (25 to 56) 7 (5 to 11) Androgen deprivation therapy 43% 67% 51% (40 to 61) 3 (3 to 4) Abbreviations defined in Glossary. RRR, NNT, and CI calculated from control event rates and relative risks in article. Commentary The RCT by Bill-Axelson and colleagues, which was done before the PSA screening era, found that RP reduced mortality. As explained by the authors, the difference between these results and those of the PIVOT trial (1) may be explained by a shorter lead time without PSA screening in SPCG-4. In todays post-PSA era, however, this information might be of interest to WW patients who receive ablative therapy in case of progression rather than at the time of diagnosis. Not all patient groups seem to benefit from a WW approach. Extensive subgroup analyses indicate that the benefits in all-cause or prostate cancer mortality are limited to patients <65 years of age and those with low and intermediate tumor risks based on Gleason scores and PSA values at study entry. These patients show favorable numbers needed to treat (NNTs). However, the authors conclude that all groups benefit, with a reduced need for prostate cancer palliation (i.e., androgen deprivation use) (NNT =3). These were not prespecified endpoints. In terms of patient-reported outcomes, urine leakage, but not erectile dysfunction, was substantial in the surgical group, with a number needed to harm of around 3. These rates may not be very different from self-reports in contemporary series of Medicare beneficiaries having robotic procedures (2) and, in my opinion, are unlikely to change sentiment on therapy. The study by Bill-Axelson and colleagues provides useful quantitative information that we can use to help patients interested in prostatectomy understand its risks and benefits.

Review: Self-testing or self-management of oral anticoagulation reduces thromboembolic events and mortality more than usual care

Source Citation Bloomfield HE, Krause A, Greer N, et al. Meta-analysis: effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes. Ann Intern Med. 2...

ACP Journal Club. Adding radiotherapy to endocrine therapy improved survival in locally advanced prostate cancer.

Question In patients with locally advanced prostate cancer, does endocrine therapy plus radiotherapy reduce disease-specific mortality more than endocrine therapy alone? Methods Design Randomized controlled trial (SPCG-7/SFUO-3 trial). Current Controlled Trials ISRCTN01534787. Allocation Concealed.* Blinding Unblinded.* Follow-up period Median 7.6 years. Setting 47 centers in Norway, Sweden, and Denmark. Patients 880 men <76 years of age who had histologically confirmed clinical stage T1bT2, G2G3, or T3, G1-3 prostate cancer (1992 TNM classification, World Health Organization grade), prostate-specific antigen (PSA) level 70 ng/mL (70 g/L), no metastases on bone scan and pulmonary radiography, good performance status, and life expectancy >10 years. Patients with nodal disease were excluded. Intervention Endocrine therapy alone (n =439) or with radiotherapy (n =436). Endocrine therapy consisted of total androgen blockade (leuprorelin, 3.75 mg/mo or 11.25 mg/3 mo, and flutamide, 250 mg 3 times/d) for 3 months, then flutamide until progression or death. Standard 3-dimensional conformal radiotherapy was started at 3 months and consisted of 50 Gy to the prostate and seminal vesicles and 20 Gy boost to the prostate. Outcomes Prostate-cancerspecific mortality. Secondary outcomes were all-cause mortality, PSA recurrence, and quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire). Patient follow-up 99% (mean age 66 y, intention-to-treat analysis). Main results At 10 years, endocrine therapy plus radiotherapy reduced disease-specific mortality, overall mortality, and PSA recurrence more than endocrine therapy alone (Table). At 4 years, groups did not differ for quality of life (P =0.059); moderate or severe diarrhea was more frequent in the radiotherapy group (12% vs 10%, P =0.003). Conclusion In locally advanced prostate cancer, adding radiotherapy to endocrine therapy reduced disease-specific and overall mortality. Endocrine therapy with vs without radiotherapy (RT) in locally advanced prostate cancer Outcomes Endocrine + RT Endocrine At 10 y RRR (95% CI) NNT (CI) Disease-specific mortality 12% 24% 56% (34 to 70) 9 (6 to 21) Overall mortality 30% 39% 32% (11 to 48) 11 (6 to 125) PSA recurrence 26% 75% 84% (80 to 88) 3 (2 to 3) PSA = prostate-specific antigen; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from data in article. 10-year data estimated from Cox proportional-hazard models. Commentary Evidence from a randomized controlled trial in early prostate cancer showed that prostatectomies improve overall and prostate-cancerspecific survival compared with no local therapy (1). However, current guideline recommendations for intermediate- to high-risk patients range from active surveillance to radiation therapy and hormonal treatments, or radical prostatectomy (2), reflecting heterogeneity in long-term prognosis. Widmark and colleagues provide the highest level of evidence in support of radiation-based treatments for such a population. The estimated relative risk reduction in prostate-cancerspecific mortality at 10 years is similar to the 56% reduction observed by the same group for prostatectomy compared with watchful waiting in early prostate cancer after a similar period (1). The 12% absolute risk reduction is clinically meaningful in this at-risk population. The trial used 3 months of total androgen blockade followed by flutamide for an indefinite period without a luteinizing hormonereleasing hormone agonist. This hormonal regimen, not commonly used in North America, is probably responsible for earlier PSA failures but should not have affected survival differences, as both groups were treated equally. The radiation treatment used is outdated but was appropriate at the time of study inception. The 2009 National Comprehensive Cancer Network guidelines recommend radiation doses up to 80 Gy (2), which is higher than that used by Widmark and colleagues. Pelvic nodal irradiation can be considered for patients at high risk for nodal metastases (2). One would expect that contemporary hormonal blockade and radiation techniques would further improve outcomes in this landmark study, but this is a condition with a long natural history, and trial results take a long time to mature.