digestive system

Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System

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Key Points

Question  For patients with advanced neuroendocrine carcinoma of the digestive system, which of the 2 community standard regimens is more effective: etoposide plus cisplatin (EP) or irinotecan plus cisplatin (IP)?

Findings  In this randomized clinical trial of 170 patients who were chemotherapy naive and had recurrent or unresectable neuroendocrine carcinoma of the digestive system, median overall survival was 12.5 months in the EP arm and 10.9 months in the IP arm.

Meaning  Both EP and IP therapy remain standard first-line chemotherapy options.

Abstract

Importance  Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC).

Objective  To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system.

Design, Setting, and Participants  This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020.

Interventions  In the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks.

Main Outcomes and Measures  The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation.

Results  Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN.

Conclusions and Relevance  Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm.

Discussion

Evidence for treatment strategies of advanced NEC is lacking owing to the rarity of the disease. Recently, the results of a randomized phase 2 trial for NEC were reported16; however, enrollment was terminated early in 66 patients owing to the premature analysis, and no definitive conclusion was obtained. The present study represents the final results of a well-designed and, to our knowledge, the first phase 3 trial with high-quality pathological diagnoses and detailed information provided by a CPR.

The primary analysis of OS revealed no statistically significant difference between arms. Therefore, it is reasonable to continue using both regimens as the standard treatment for NEC. We were interested in the effect of pathological findings and primary organs on treatment efficacy. Although the results showed no statistically significant differences in any subgroups, the overall impression had a greater interaction by primary organ than by pathological findings in terms of OS and PFS (Figure 3 and eFigure 5 in Supplement 1). Because platinum regimens have been reported to be less effective in grade 3 NETs,5,8 and the WHO 2017 classification system9 and 2019 classification system10 formally declared grade 3 NETs as a separate entity from NECs,9,10 subgroup analyses of PDNECs only are of relevant clinical interest. Subgroup analysis of OS in PDNECs only indicated weak tendency of preferred results in the EP arm over the IP arm. A subgroup analysis of only PDNECs in each primary tumor indicated that the OS of the EP arm was better than that of the IP arm in the subset of pancreatic PDNEC. Although post hoc subgroup analyses should be interpreted with caution, these results have important implications. The CPR indicated that pancreatic NECs are characterized by a higher proportion of small cell carcinoma and a lower proportion of tumors with non-NEC components (eTable 2 in Supplement 1). Although these characteristics may have influenced the unique results in this subgroup, they cannot fully explain this phenomenon.

In terms of AEs, grade 3 and 4 AEs such as myelosuppression and FN were more common (>2 times) in the EP arm. Although these AEs were generally manageable, the high incidence of FN remains a point of caution. We took note of the high incidence of FN during this trial in the monitoring report; therefore, we revised the protocol to recommend primary prophylaxis with G-CSF32,33 after October 31, 2017. In the exploratory analysis of this study, prophylaxis with G-CSF seemed to effectively decrease the incidence of FN. However, considering higher planned/actual DI and lower relative DI in the EP arm, and higher rate of treatment termination owing to AE or patient’s refusal (third dose reduction owing to neutropenia), lower initial dose of EP therapy may be appropriate.

In addition to the outcome of the clinical trial, this study is very valuable in its provision of information on high-quality pathological diagnoses made by consistent CPR panel members throughout the entire period. Notably, the pathological diagnosis was not consistent with that of the participating institutions in nearly 10% of cases, indicating the difficulty of an accurate pathological diagnosis of NEC. Additionally, detailed information about the pathological findings was obtained for the cross-organ manner, which itself is an important asset in the field of NEC. In the forest plots of OS and PFS, the difference between EP and IP among the CPR subgroups was smaller than that of the primary organs (Figure 3 and eFigure 5 in Supplement 1).

Limitations

This study has some limitations. Although the primary analyses revealed no statistically significant difference in OS between the 2 arms, the study was not designed to assess the equivalence of the 2 regimens. Therefore, the 2 regimens should not be recognized as equivalent, but rather as they do not differ beyond a certain level. In addition, in patients diagnosed via results of biopsy specimens, accurate information of the entire tumor could not be obtained with respect to proliferative activity or the proportion of non-NEC components. In this study, patients diagnosed by biopsy harboring any proportions of non-NEC components, as long as a harboring NEC component was allowed to be enrolled, means that theoretically a certain percentage of patients with mixed adenoneuroendocrine carcinomas were enrolled. These limitations were unavoidable considering the diagnostic procedure, and this is also a universal issue in daily practice. Additionally, because further effects of immune checkpoint inhibitors on platinum regimens has been proven in small cell lung carcinoma,34,35 it is the next important clinical question in NECs.

Conclusions

Results of this phase 3 randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy regimens for advanced digestive NECs. Post hoc subgroup analyses pointed to the superiority of EP in pancreatic PDNECs, and EP was safely given along with the use of primary prophylactic G-CSF.

Source: JAMA

WHY EATING LATE IS HARMING YOUR HEALTH

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LateNightSnacking(1)

Could those late night snacks be adding to your waistline and causing harm to your heart? A new study suggests that its better to eat during the daylight hours.

Nighttime snackers take note: eating late is harming your health, or so suggests a recent study out of San Diego State University.

While the study looked at fruit flies, and not humans, the findings do provide compelling reasons to investigate further whether there is a causal link between late night eating and heart health, amongst other health measures. I have been saying for some time, it is not just WHAT you eat, but WHEN you eat too.

Two-week-old fruit flies were divided into two groups: one group was allowed to eat a standard diet of cornmeal at anytime they wished and the second group was restricted to eating only within a twelve hour period. The amount of food each group ate was comparable. At the end of a three-week period, each fruit fly was measured on several health measures, including weight and heart health. Fruit flies on a restricted schedule were found to have stronger hearts, better sleep patterns, and to have gained less weight than their eat-anytime friends.

The results were the same when repeated at five weeks and when the study was completed with older fruit flies. What is it about late-night snacking that compromises our health, including our heart and waistline?

  • Your body’s digestive system works hard each day to process the food you put into your mouth. Nighttime fasting—as I define it, no food after 7pm—allows your digestive system to take a much-deserved rest. Your stomach takes several hours to empty. A dinner or snack after 7pm likely doesn’t have time to make it through the system before you fall asleep.

  • Intermittent fasting is actually good for your body, in particular for individuals who are obese or have high blood pressure. Our ancestors went through periods of famine; it is natural to assume our body functioning accommodates times of food scarcity by working more efficiently. Fasting is thought to regulate the body’s hunger hormone (ghrelin), which can be out of whack for many people facing obesity. It also works as a reset button for your body: giving you a chance to clear out toxins and regulate insulin levels.  It can be  for those who require high-level intervention.

  • Allowing your digestive system to “take a breather” promotes better sleep.

  • Most of us are fairly sedentary after 7pm. Calories consumed past this time are more likely to be stored as fat, because our body does not have time to burn them off before we hit the hay.

    And then there is heart health, something our fruit fly researchers suggest is important to continue examining (I agree). Another preliminary study, this time on humans, found that men who ate late at night were 55% more likely to develop coronary heart disease.

We can all benefit from restricting our food to the daylight hours. The best health advice I can give my patients who seek weight loss support is to consume their most caloric meals earlier in the day, then start to slow consumption towards the end of the day to give the body time to rest, and to ensure that calories consumed have a chance to fuel the body. We also make poor food choices at night; fatigue makes us prone to cravings. Ditch the late-night snacking habit and improve your heart health and waistline.

Candida overgrowth – 12 things you absolutely need to avoid if you have it .

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Proper management of the digestive system could easily be one of the most important health practices one can do on a day-to-day basis in order to obtain good health. However, a severely compromised food supply and chemical filled world has made it very difficult to achieve that important goal. This in turn has encouraged the overgrowth of digestive disturbances like candida (yeast) overgrowth, which can only be effectively managed by first eliminating these 12 things.

candida

Antibiotics and birth control pills

Antibiotics may be the single biggest cause of candidiasis due to its non-discriminatory killing of “good” intestinal bacteria, as well as “bad” infection-causing bacteria. This alters the balance of intestinal flora and suppresses the immune system, which makes one more susceptible to candidiasis and bacterial infections, which can lead to more antibiotics and the increased growth of candidiasis.

Sugar

Candida thrives on sugar, which makes it one of the more important things to eliminate when dealing with a candida overgrowth. This includes natural sugars found in sweet fruits (such as bananas, oranges, pineapples, peaches, and mangoes), and naturally occurring sugars in honey, molasses, maple syrup, and rice syrup.

Alcohol

Alcohol is high in sugars that can feed a candida overgrowth, and it also puts stress on the immune system, which needs to be healthy in order to eliminate a candida overgrowth. Alcohol like beer and wine are also loaded with glutinous grains and yeast, which further exacerbate the condition.

Gluten

Gluten is incredibly difficult to digest and as a result can create call kinds of digestive disturbances and toxic reactions that feed an improper balance of intestinal bacteria, which fosters candida overgrowth.

Dairy products

Milk contains lactose, a type of sugar that promotes candida overgrowth. Almost all dairy should be avoided, with the exception of ghee and butter. Small amounts of raw, sugar free dairy kefirs and yogurts are sometimes permissible due to lactose being largely consumed during the fermentation process.

Pork and processed meat

Pork contains retroviruses that survive cooking and can be harmful to those with a weakened digestive system. Process meats often contain nitrates, sulfates, and sugars, all which contribute to a candida problem.

Caffeinated beverages

Caffeine can cause blood sugar to rise, weakens the adrenals, and impairs the immune system, which promotes candida overgrowth. Coffee can also contain mold, which is problematic with a fungal infection like candida.

Most seafood

All shellfish and most fish contain high levels of heavy metals and toxins, which repel good bacteria and facilitate a candida overgrowth. Avoid farmed salmon, and stick with wild caught.

Certain nuts

Cashews, peanuts, and pistachios contain a high amount of mold, which can exacerbate an existing fungal (mold) problem like candida.

Beans and other legumes

Beans are very difficult to digest and high in carbohydrates. This puts beans off the list in the early stages of candida elimination. Soy is completely off limits, unless it is organic and fermented.

Mushrooms

If you are suffering from an excessive candida issue, some fungi can cause an inflammatory reaction. However, some medicinal mushrooms like reishi and maitake actually have an antifungal effect and boost the immune system.

Vinegar

Vinegar is made primarily from GMO corn, and is made in a yeast culture. This depletes the stomach of acids and can cause further inflammation in the gut. The only exception is unfiltered apple cider vinegar, which can help combat a candida overgrowth due to its probiotic and enzyme content.

Fats and oils

Peanut, corn, and canola oil are contaminated with mold, and most soybeans used in soy oil are GMO. It should be noted that the corn and canola used in oil are largely GMO as well.

To learn more about a simple home test to see if you have candida, and what to start to do to get it under control, visit the first source below. Check out 5 Superfoods that Can Help Heal your Gut and How to Kill Candida and Balance Your Inner Ecosystem.

Sources for this article include:

http://www.healingthebody.ca

http://www.healingthebody.ca

http://www.thecandidadiet.com

http://www.rodalenews.com

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