Kidney

There is a growing list of supplements, over the counter drugs and even functional foods that can deliver measurably improved treatment responses and help managing the side effects. Its striking that the impacts reported are usually more than can be achieved by adding more oncology drugs to a treatment plan, and crucially there are often a reduction in side effects.

Analysis of prescription records in Scandinavia has reported reduced progression rates in patients taking antihistamines, especially desloratadine. Similar studies have confirmed these impacts in immunotherapy too. Also from case data studies, those with higher vitamin D3 levels before and during therapy also get better outcomes, and researchers increasingly call for trials to develop use of vitamin D3 further. In other cancers, higher doses have been needed to move levels from deficient to relatively high. Cancer activity including associated inflammation and oncology treatments decrease levels of crucial nutrients such as D3 so there is a constant drain.

Low dose aspirin does have more ongoing trials, including those showing increased response levels to immunotherapy including nivolumab and with mTOR inhibtors e,g everolimus. Aspirin can also help reduce hyper active blood platelet activity that drives “stickiness” and clotting, but elevated levels are known to increase metastasis. Also in ongoing cancer research are statins, where there is some evidence of reduced progression, especially in patients that respond to stain introduction with lowered cholesterol. Statins have multiple cancer suppressing actions and red yeast rice can be used when no prescription is available. Crucially, statin user during immunotherapy are reported with risk reductions of a half or so.

Mushroom glucans in turkey tail extracts have fascinating case study reports in kidney cancer management. Boosting and balancing immune system responses with beta glucans is a growing area of research, many good options are available including turkey tail. Useful additions to most oncology treatment, including helping immunotherapy response and reducing side effects. Also in immunotherapy, relatively high circulating sodium has recently emerged as a predictive marker for high responders. Studies of data from large trials in metastatic kidney cancer management show remarkably better outcomes in the on third or so of patients with higher natural sodium. The commonly available anti-aging supplement alpha ketoglutarate is emerging in cancer research too for similar reasons. Based on clinical evidence in melanoma patients, higher relative levels increase immunotherapy response. Supporting lab data for kidney cancer shows unusually clear evidence.

A recently expanded phase I study in Iowa, USA, supporting TKI axitinib therapy and “high” dose organic L-selenomethionine supplements. Perhaps the most significant metabolic pathway dysfunction in kidney cancer progression is HIF1α/2α (hypoxia), and here there is a striking pilot study where readily available selenium L-selenomethionone is reportedly working with TKI therapy to significantly increase drug uptake and remission rates. Other studies have highlighted the importance of selenium/zinc ratio, both are needed.

Dysfunctional iron metabolism is common during cancer and with oncology treatments, and kidney cancer is the leading example. Iron deficiency is common in patients, and is linked to poor prognosis. On the other hand, the tumor environment is rich in iron stored by high levels of the enzyme like protein ferritin. Higher ferritin is linked to increased cancer activity levels. Lactoferrin is a prebiotic class milk protein which can restore iron balance, improving both absorption and healthy distribution of iron. This can potentially suppress iron related cancer growth. The milk based prebiotic lactoferrin has some compelling patient case studies. Also related to metals, high serum levels of copper especially with insufficient zinc are very strongly linked with poor prognosis. One possibility reported is cancer switches the metabolism to free up copper for its needs to grow and spread rapidly, and down regulates zinc and selenium. Heavy metal detoxification has been shown in patient cases with use of citrus pectin, ideally with marine alginates. Related, citrus pectin trials show improved outcomes based on reducing glucose based growth mechanisms, so called galectin-3 proteins. Lower levels are linked to strongly lowered progression risk.

Increasing evidence is emerging on the crucial impacts of gut bacteria strains such as akkermansia. Good natural levels improve success with TKI therapies such as carbozantinib or axitinib. Along with these bacteria strains, the presence of inosine both natrually and supplemented has growing evidence of improving the response rates of immunotherapy. Related, there are ongoing trials for use of ketogenic diets and supplements such as MCT oil and beta-hydroxybutyrate for supporting immunotherapy responses https://clinicaltrials.gov/study/NCT05119010

Other well defined metabolic dysfunctions relate to increased fatty acid metabolism. Berberine has good evidence of improving this higher lipid metabolism including these fatty acids used by cancer to grow, while Urolithin A is emerging from anti-aging science as a credible natural supplement able to counter some of these mechanisms. Systemic inflammation is linked with increased risks for progression, especially in later stages. Both acute type inflammatory responses measured by C-reactive protein, and immune system related neutrophil-to-lymphocyte ratios. Maintaining relatively lower levels of both make a substantial difference. Commonly used Astragalus root has evidence of improving immune system balance and NLR while curcumin and other other functional foods including garlic can reduce this inflammation. Astragalus has shown strong supportive benefits in patient data, including lung cancer.

High dose melatonin also helps some late stage relapsed patients including kidney cancer. New research into advanced stage outcomes of immunotherapy shows substantial benefits to AM treatment vs PM of 43% improved survival rates https://jitc.bmj.com/content/12/3/e008011

The so called Th1/Th2 immune system balance is strongly linked to the progression and to treatment resistance. Molecular iodine solutions are emerging in this area in breast cancer management and seen boosting Th1 anti tumor activity and helping suppress over active Th2 used in resistance. The has improved results in surgery plus chemotherapy and may support increased response immunotherapy (see Supplement Library)

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Antihistamines have increasing evidence for their positive impacts

A relative reduced risk of 30% for 180 cases seen from records of prescription use
Desloratadine is highlighted for its impact in kidney and other cancer progression
Its suggested these effects would improve immunotherapy responses.

Desloratadine use was associated with an improved survival for all immunogenic tumors, but not for the non-immunogenic ones. Loratadine use was associated with improved survival for some tumors…We believe that there is already a compelling case for further studies of H₁-antihistamines as potential cancer treatment, as well as for initiation of clinical trials of mainly desloratadine and loratadine…Based on what we present here, that pool should be extended to include at least all other immunogenic tumors in our study and priority should be given to trials of deslorata...

Aspirin has a majority of analysis in its favor including all-cause risks

A 47% increased response rate and 21% longer progression free times
A relative risk reduction of 15% , only statins having similar effects in this data
Multiple other drugs especially antibiotics reported negative impacts

This study included consecutive patients with confirmed diagnosis of stage IV solid cancer, who underwent treatment with single agent anti-PD-1/PD-L1 as first or subsequent line, with data availability regarding baseline concomitant medication…The relationship between aspirin and cancer prevention/progression have been historically known, but in the setting of immunotherapy of cancer, few studies have been published. Even if (cyclooxygenase) COX-2 expression was known to be positively associated with PD-L1 tumor expression,46 we did not find associations between baseline NSAIDs (exclu...

Turkey tail direct results of some fascinating patient case studies

2 patient cases with advanced stage disease show much slower progression
A reputable integrative oncology clinic reporting on use of mushroom supplements
The researchers call out a need for more research into turkey tail beneifts

Beneficial effects of integrative care were observed in this case series. Disease progression and symptoms related to adjuvant treatment were significantly decreased in these patients after integrative supportive care was initiated and effects persisted through the final observation period. Further controlled studies are needed among larger groups of patients to determine the clinical efficacy of medicinal mushrooms and integrative oncology in the treatment of RCC…Integrative medicine research that includes a whole systems approach with a focus on quality of life and extended survival...

Red Yeast Rice or a prescription statin have multiple benefits including all cause risks

In advanced stage patients statin use reduced relative progression by a quarter
Particularly up to 25% with TKI therapy such as sunitinib, axitinib, carbozantinib
Lovastatin from red yeast rice is shown in multiple cancers as an effective option

We demonstrate that statin use may be associated with improved survival in patients with mRCC [metastatic renal cell carcinoma] treated in the targeted therapy era… Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.80….a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months), aHR 0.75 [a 25% risk reduction]

Citrus Pectin removes heavy metals such as copper and has its own anti-cancer mechanisms

Patients with serum levels higher in zinc and, above all, low in copper show > 10X reduced risks
Low relative copper level reduced risk 7.5X for women and 5.4X for men for all cause mortality
Researchers discuss stratgies are needed to reduce copper and maintain zinc

We found that patients with the highest copper levels and lowest zinc levels had significantly higher all-cause mortality. This study revealed a significant association between a low Zn/Cu ratio and increased mortality.
We observed that patients with low blood/serum copper levels had significantly better survival rates compared to those with higher levels.Examining the Zn/Cu ratio, we observed that a higher zinc/copper ratio was associated with significantly better survival rates. What is of particular value is that analysis of the Zn/Cu ratio in both whole blood and serum allows for ...

Alpha ketoglutarate anti-aging supplements are developing research including immunotherapy

Higher alpha-ketogluarate levels give much higher response to immunotherapy
Readily available, well tested and highly absorbed anti-aging supplement
Compelling pre-clinical models show reduced evasion of therapy in kidney cancer tumor

Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in an...

Lactoferrin increases iron balance and reduces anemia rates, countering cancers use of iron

Direct evidence is limited to some high quality patient case studies
Phase II trial where 1/4 of patients experienced much extended survival
Reductions in both primary and metastatic lesions are reported in patients

Following a successful phase I trial, it was administered orally to patients with metastatic renal cell carcinoma (RCC) in a phase II trial conducted at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, among other sites. We report a case series of 4 patients treated at our institution with very encouraging progression-free survivals, all exceeding 30 months, in order to suggest that this agent merits further study. These four patients with radiographically progressive metastatic RCC received single-agent oral lactoferrin in daily doses of 9 grams, given in cycles of...

Sodium levels are rapidly emerging as a key biomarker during immunotherapy

A dose dependent effect in immunotherapy, higher natrual levels >400mmol/L by far best
Almost 10X increased odds of complete responses in the third of patients vs low levels (about 15%)
Predicts treatment success more closely than the established biomarkers even PD-L1 expression

Mechanistically, the current literature suggests that sodium sustains the antitumor immune response, which appears to be consistent with the results of our study. However, causality cannot be inferred from our post-hoc analysis and further investigation is needed. Independent of causality, the strong association of sodium concentration with response to immunotherapy and favorable outcomes, especially when compared to TKI and chemotherapy, should be further investigated for its potential for therapy stratification. In addition, a higher target serum sodium level in ICI-treated patients could...

Akkermansia gut bacteria levels often linked to improved response in oncology, especially immunotherapy

Improved outcomes in TKI therapy with higher bacteria of types akkermansia and barnesiella
Clear association to those patients with less than half the relative progression risks
The probiotic yoghurt used was not the driver for the naturally higher levels

Our randomized, prospective study demonstrated that dietary interventions result in modulation of gut microbiome in patients with metastatic renal cell carcinoma receiving VEGF-TKI therapy [eg carbozantinib, axitinib etc]. In addition, this study is the first to suggest that components of the stool microbiome, A. muciniphila and B. intestinihominis, may predict clinical benefit in patients with mRCC receiving VEGF-TKI therapy, distinct from previously reported predictors of checkpoint inhibitor response. We also demonstrate proof of principle, with the active ingredient of our prob...

Selenium here is particularly interesting for its fascinating pilot studies at high doses

Phase I trial with L- selenomethionine intervention from 2500 – 4000ug
Almost 56% response rate with TKI axitinib in these 27 previously treated patients
Progression free survival 15 months, overall survival 20 months very promising

Patients were treated at the 4000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy…No dose limiting toxicities occurred at the 4000 μg SLM dose level. Among the 27 patients treated with 4000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months..Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1, and stabilization of tumor vasculature by SLM are time dependent

Zinc levels need maintaining at healthy levels according to patient data in many cancers

Pre-diagnostic levels of both selenium and zinc linked to better outcomes
The effects found were much larger for men, unlike the general case in cancer
Something to consider if supplementing with selenium for instance

This prospective study of 284 kidney cancer patients showed the correlation between selenium blood/serum levels and 10-year survival. For blood samples, the HRs were higher for selenium levels and all-cause mortality rates compared to serum samples….This was more significant (7-fold greater) in men compared to women. There was a significant correlation found when we combined selenium and zinc levels…the current study showed that high levels of selenium in blood/serum, combined selenium and zinc levels (SeQI-ZnQI vs. SeQIV-ZnQIV) and zinc-to-selenium ratio predispose kidney cance...

Urolithin A increases healthy cellular behaviors that may reduce cancers upregulated fatty acid metabolism

Evidence kidney cancers increase fatty acid lipids to fuel growth
Data shows over 3X increased levels of key markers of this activity in RCC
Several compounds including Urolithin A may help reduce this activity

It is of high importance to state that that this compound was also found in urine samples from cancer patients at three times higher abundance compared with controls. Thus, it is a very good candidate for a new kidney cancer biomarker. Acylcarnitines, which are intermediates in the key energy metabolic pathways of fatty acid β-oxidation and amino acid catabolism, were found previously at higher concentrations in tumor tissues and urine as compared with a set of matched control patients without RCC..Additionally, some studies have reported that several carnitine-type metabolites could also ...

Berberine evidence in metabolic health may help counter cancers use of lipids and sugars to grow

Elevated levels of TIGAR protein driven sugar metabolism affect over 60% of patients
Patients with relatively low levels saw higher increased survival rates especially early stage
Berberine research shows it strongly binds TIGAR in its glucose clearing actions

In our study, positive TIGAR expression was found in 61.29% (38/62) of clear cell RCC patients. The increased TIGAR protein level was associated with older age, venous tumor thrombus, and higher SUVmax [measure of kidney function] in our cohort. More importantly, a shorter survival time was found in clear cell RCC patients with positive TIGAR compared with those with negative TIGAR expression (HR=3.62). Previous studies have suggested that TIGAR plays a role in tumor progression by regulating tumor burden and redox homeostasis

Oat and egg based functional foods are entering early stage clinical trials for several cancers

Many tumors show elevated internal fluid pressure that drives growth
Kidney tumor analysis here confirms in detail the bio-physical barrier to therapy
Functional foods may deliver or stimulate effect anti-inflammatory response

Most tumors included a dense vascular network and parts devoid of vessels in necrotic areas…these tumors had a high vascular resistance.. In conclusion, the vascular density does not translate into degree of perfusion. Tumor areas with an extreme vascular density are often poorly perfused compared to cortical tissue with a less dense network. Tumors develop an increased interstitial fluid pressure, compressing the thin-walled tumor vessels, which results in reduced circulation…We speculate that this might curtail access to the cancer by therapeutic agents and require further stu...

Curcumin has evidence for reducing levels of systemic inflammation used by cancers

Across 44 trials a strong link is reported for inflammation (c-reactive protein)
Low inflammation or CRP levels reduced post-nephrectomy risks over 70%
In more avanced stage disase approximately half the risk level

In our meta-analysis, we evaluated the association between CRP and survival outcome of patients with different tumor stages or treated with different therapies. As we expected, the prognostic role of CRP was also confirmed in localized RCC treated with surgery, metastatic RCC treated with targeted therapy. Interestingly, the cutoff value of CRP should be carefully selected based on our results of meta-regression analysis. For CSS, the higher the cutoff value of CRP was, the higher HR was

Astragalus actions include protecting and balancing immune responses often with clear effects reported

Meta-analysis reported half the risk levels for lower immune related inflammation
Neutrophil-to-Lymphocyte, NLR, ratio even more crucial in metastatic stages
Astragalus has evidence of reducing NLR including immunotherapy

Thus, the aim of this systematic review and meta-analysis of 6461 RCC patients was to clarify the prognostic value of pretreatment NLR in RCC patients. The results indicated that elevated pretreatment NLR was significantly associated with poorer OS, DFS, and CSS in nonmetastatic RCC patients. Similarly, high pretreatment NLR also showed significant association with worse OS and PFS in metastatic RCC patients. To further explore the source of heterogeneity, we performed subgroup analyses according to the features of enrolled studies, which also demonstrated the stability and reliability of o...

Melatonin trials have shown longer survival rates, even in late stages, and improved side effects

Immunotherapy outcomes showed much longer progression free survival
The report also describes extended overall survival
Melatonin has been reported safe at very high dose levels

Patients were randomized to receive morphine alone or morphine plus MLT (20 mg/day orally in the evening)….The percent of partial responses achieved in patients treated with morphine alone was significantly lower than that observed in patients concomitantly treated with MLT (1/16 vs. 4/14). Moreover, the 3–year percent of survival was significantly higher in patients concomitantly treated with MLT

Inosine trials are few but some early promise with immunotherapy

A 57% improved response to immunotherapy with higher inosine levels
Clinical trial data has shown similar effects for lung cancer with direct supplementation
A trend to reducing some of the side effects of immunotherapy

Our results demonstrate that inosine overcomes tumour cell-intrinsic resistance to immunotherapy by inhibiting UBA6 in tumour cells to enhance tumour immunogenicity (Fig. 7). We identify UBA6 functions as a tumour-intrinsic checkpoint that limits antitumour immunity and implicate UBA6 as an attractive target for immunotherapy. Together with recent studies25,47, our findings highlight the potential application of inosine in combination with ICB for cancer patients with high UBA6 expression.

Vitamin D3 has a broad body of evidence in cancer management

Most patients were deficient in D3 prior to immunotherapy
In the supplementation group the risk reduction was a half
This in effect doubled the response and survival times

Our study provides for the first-time practice informing evidence about the high prevalence of hypovitaminosis D in patients with solid tumors treated with ICI and on the efficacy of systematic supplementation to timely restore adequate vitamin D levels in most patients. Our explorative comparative analysis offers provocative insights about the putative multifaceted immune-modulating effects of vitamin D systematic supplementation, which could potentially improve clinical outcomes and prevent thyroid irAEs in patients receiving ICI-based treatments

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GUIDE

Pathfinder Element	Risk Reduction Factor	Anti-Metastatic	Reduces Side Effects	Research Study
Lactoferrin	>50%	Probably	Yes	Link
Sodium with immunotherapy	>50%			Link
Alpha ketoglutarate with immunotherapy	>50%		Maybe	Link
Red yeast rice/ statin	>50%	Probably	Maybe	Link
Vitamin D3	>50%	Yes	Yes	Link
Gut health including Akkermansia	>50%	Probably	Yes	Link
Zinc (during immuotherapy)	>50%	Maybe	Maybe	Link
Beta glucans	26 - 50%	Yes	Yes	Link
Antihistamines (including with Immunotherapy)	26 - 50%	Probably	Probably	Link
Selenium (possibly higher doses)	26 - 50%	Probably	Maybe	Link
Turkey tail	Up to 25%	Yes	Yes	Link
Aspirin	Up to 25%	Yes	Maybe	Link
Melatonin with immunotherapy	Up to 25%	Maybe	Yes	Link
Astragalus	Indirect - High	Yes	Yes	Link
Inosine	Indirect - High	Maybe		Link
Oat and egg functional foods	Indirect - High	Probably	Yes	Link
Citrus Pectin	Indirect - High	Probably	Probably	Link
Berberine	Indirect - High	Maybe	Maybe	Link
Urolithin A	Indirect - Moderate	Maybe	Maybe	Link
Curcumin	Indirect - Moderate	Maybe	Maybe	Link
Vitamin B3	Indirect - Moderate	Maybe		Link

Plan Item	Cancers	Background Details	Trial Doses Under Supervision	References
Antihistamines	Breast, TNBC, Prostate, Lung, Colorectal, Kidney, Liver, Gastric, Ovarian, Cervical, Pancreatic, Melanoma, Lymphoma, Esophageal, Bladder	Research indicates desloratadine for localized cancers or loratadine for metastatic. There are examples of ebastine or other alternatives in certain cases. Growing research evidence indicates improved oncology responses. Taken between meals. Low histamine before and during treatment is beneficial.	Active use in clinical trials is still in early phase, follow the dose recommendation for instance 5mg daily unless under medical supervision where higher 10mg doses are frequent
Aspirin	Breast, TNBC, Prostate, Lung, Colorectal, Kidney, Liver, Ovarian, Cervical, Endometrial, Pancreatic, Melanoma, Myeloma, Head and Neck, Bladder, Gallbladder, Non Melanoma Skin, Gastric	Use of low dose 75 or 81mg "baby" aspirin is reported to benefit many cancer types across an average study group, and even all cause mortality. There are some indications of specific "responders" for instance those with existing inflammatory conditions or certain gene expressions. With food.	In a colorectal cancer trial responders were tied to the expression of particular genes (PI3KA). Doses were 160mg	LINK
Astragalus	Breast, TNBC, Lung, Colorectal, Liver, Gastric, Cervical, Endometrial, Pancreatic, Prostate, Kidney, Ovarian, Glioblastoma, Non Hodgkin, Lymphoma, Leukemia, Myeloma, Head and Neck, Bladder, Gallbladder, Thyroid	A typical astraglaus membranaceus supplement may have 50mg of astragaloside IV the main active compound. Its possible with meals can reduce any stomach upset. Use of a standard dose to help immune system balance before treatment.	Here, Astragalus is added to standard oncology in lung cancer Doses are 2-3 tablets of 250mg AMe (Solgar, NJ, USA) minimum for 6 months in this example	LINK
Beta Glucans	TNBC, Lung, Liver, Gastric, Cervical, Pancreatic, Melanoma, Non Hodgkin, Lymphoma, Leukemia	There are many options for mushroom or yeast 1,3/1,6 glucan and branded products include California Gold Immune Defense/Wellmune, AHCC, Biogen/ Yestimun, ImmiFlex, IP6 and many more. A pharma grade product, odetiglucan, is continuing in trials. Take on an empty stomach. Use a standard dose to help balance the immune system before starting treatments.	AHCC is used at 3x1g per day over several months during treatment. Beta glucans are used at 1-2g per day and higher.	LINK
Danshen	Breast, Prostate, Lung, Colorectal, Liver, Leukemia, Myeloma, Bladder	The most common chinese herbal medicine in oncology, also known as red sage. Premium brands such as MCS may recommend 1g twice daily as an ongoing dose. Its possible with meals can reduce any stomach upset. Start a standard dose a couple of weeks before treatment to help balance the immune system.	3 x1g daily between meals , over at least 90 days ideally longer to get maximum benefits according to reported patient outcomes, though even shorter dose period reduced risk	LINK
Green Coffee Extract	Glioblastoma	Supplements vary in terms of their chlorogenic acid content, it can be up to 50%. Quality brand might specify this level under their recommended intake. High dose commercial brands may be over 1000mg total, take before meals.	Analysis across trials reports metabolic health benefits start are higher at >500mg or daily. High chlorogenic acid content supplements eg Svetol have been trialed safely for 12 weeks at 200mg x 5 daily dose. As always, be aware of possible drug interactions	LINK
Red Yeast Rice Or statin	Breast, TNBC, Prostate, Lung, Colorectal, Kidney, Liver, Gastric, Ovarian, Cervical, Endometrial, Melanoma, Leukemia, Myeloma, Head and Neck, Esophageal	Red yeast rice is equivalent to lovastatin. Doses are essentially on the products, and there are many premium brands with guaranteed level of monokolin k around 3mg. A common theme is findings is those with improved cholesterol are "responders". With meals. Start cholesterol and inflammation reducing statins early.	Trial data is often case studies with multiple statins where lovastatin has average effects. Often atorvastatin and sometimes simvastatin come out on top. Research ususally reports intermediate doses ( 10-20mg) are effective but there are examples indicating higher doses under supervision.	LINK
Turkey Tail	Lung, Colorectal, Kidney, Liver, Gastric	A typical premium supplement such as MCS recommend 700mg twice daily with food. Mushroom based glucans can help balance immune response so start them before your treatment.	Pharma grade turkey tail, e.g PSP/ PSK/ Krestin is typically used at 3x 1g daily during oncology, up to 36 months and more. Trials in breast cancer have also used 3,6 and 9g daily regimes in 6 week periods	LINK
Vitamin D3	Breast, TNBC, Prostate, Lung, Colorectal, Gastric, Ovarian, Pancreatic, Glioblastoma, Melanoma, Non Hodgkin, Lymphoma, Leukemia, Myeloma, Head and Neck, Esophageal, Bladder	High dose commercial formulae can be 10,000IU. Which might be achieved by as little as 10 to 20 minutes in sunshine. Vitamin K2 is advised with D3. Take with some food containing fat. Its important to ramp these up before oncology treatments, and sustain the higher levels over time. Add magnesium for best absorption and metabolism.	The VITAL trial used 2000IU and discussed the potential of higher doses to increase responders especially higher BMI/ body weight. Whilst in prostate cancer there are trials demonstrating at least 10,000IU is required to see activity reducing PSA levels	LINK
Melatonin	Breast, TNBC, Prostate, Lung, Kidney, Liver, Ovarian, Cervical, Endometrial, Pancreatic, Glioblastoma	Commonly used in 10 to 40mg daily range no reported side effects, typically an hour before sleep.	Moderate and high dose trials report no significant side effects even at 1000mg daily	LINK
Citrus Pectin	Breast, TNBC, Prostate, Lung, Colorectal, Kidney, Liver, Ovarian, Cervical, Endometrial, Pancreatic, Non Hodgkin, Leukemia, Myeloma, Head and Neck, Esophageal, Bladder, Gallbladder, Thyroid, Gastric	Trials use a recommended dose up to 5g x3 daily and no significant side effects. Taken 30 minutes before or 90 minutes after food. Ideally, start PectaClear or similar products at least 4 week before treatment to reduce heavy metals. But sustain zinc with supplementation	Even in children age 5 to 12 the daily regime 3 x 5g was safe and effective for heavy metal chelation	LINK
Soy Isoflavones	Breast, Prostate, TNBC	Often dietary sources, tofu and soy based and no evidence of side effects. Supplements generally with food.	In a clinical trial setting up to 900mg with no issues	LINK
Fermented Wheatgerm	Prostate, Colorectal, Melanoma	Trials are with Avemar brand products with no significant safety concerns reported	Typical dose regimes may be aroung 9g daily over longer time periods for instance 12 months	LINK
Iodine	Breast, TNBC	General usage around 1000mcg or 1mg generally with food	Successful pilot studies in breast cancer use 5mg molecular Iodine daily for the duration of therapy	LINK
Lactoferrin	Breast, TNBC, Prostate, Lung, Colorectal, Kidney, Liver, Gastric, Ovarian, Cervical, Endometrial, Pancreatic, Glioblastoma, Melanoma, Non Hodgkin, Lymphoma, Leukemia, Myeloma, Head and Neck, Bladder, Esophageal, Gallbladder, Thyroid	200mg typical use daily , eg 10ml liposomal formula ideally 30 minutes before meals or 2 hours after. No side effects of note. Start this immediately to achieve and maintain healthy iron absorption, avoid deficiencies and reduce cancer related ferritin levels.	During oncology doses of up to 3g to 9g daily, even higher, have been used with significant side effects	LINK
Selenium	Breast, Lung, Kidney, Ovarian, Cervical, Endometrial, Pancreatic, Melanoma, Head and Neck	Supplements are 200ug doses and similar amounts from about 3 brazil nuts. Start buildin gup your levels immediately and keep them high during oncology. Selenium toxicity is a consideration for high doses over time, so seek medical advice. Ideally taken with meals.	This trial used 2500 to 4000ug 2x daily for 14 days then once daily in kidney cancer with no dose limiting toxicity	LINK
Vitamin B3	Liver, Gastric, Glioblastoma, Non Hodgkin, Lymphoma, Leukemia, Non Melanoma Skin	Typically 500mg for nicotinamide (niacinamide) form of B3 taken ideally with meals	Do not differ from standard doses, here 500mg twice daily related to skin cancer	LINK
Akkermansia	Breast, TNBC, Prostate, Lung, Kidney, Liver, Ovarian, Cervical, Pancreatic, Non Hodgkin, Lymphoma, Leukemia, Myeloma, Head and Neck, Gastric	Commercial products may be at 10B CFU typically 30 minutes before or 2 hours after food. Ramp up levels with diet and moderate supplementation before treatments, especially immunotherapy.	Under development. Results in oncology indicate this is one of many helpful guy bacteria. careful consideration and particularly following use of antibiotics. Diversity is crucial.	LINK
Berberine	Kidney, Liver, Cervical, Pancreatic, Non Hodgkin, Leukemia, Myeloma, Head and Neck, Esophageal, Gallbladder, Thyroid, Non Melanoma Skin, Melanoma, Bladder	A natural anti-diabetic used frequently at 400mg daily and above, shortly before meals	In metabolic health trials frequentlu use up to 500mg at 3 times daily .	LINK
Curcumin	Colorectal, Liver, Non Hodgkin, Myeloma, Bladder, Gallbladder, Non Melanoma Skin, TNBC, Breast, Prostate, Lung, Kidney, Gastric, Ovarian, Cervical, Endometrial, Glioblastoma, Melanoma, Lymphoma, Leukemia, Head and Neck, Thyroid	Doses from 500mg to 2000mg frequently seen. Piperine fron black pepper improves absorption, highly bioavailable formulae are available. Ideally with a meal containing fat.	Higher doses in trials are frequently 2 of 4 g daily (+40 mg piperine) during oncology for instance here at 3 periods of 30 days	LINK
Quercetin	Glioblastoma, Myeloma	Can be found in a healty diet. Supplements often 500 or 1000mg and can be taken with tocotrienols for enhanced absorption, a form of vitamin E . Some evidence that Quercetin should be pulsed on/off.	Clincial trials have safely used up to 5g daily in adults, and 1 to 4g for rare forms of paediatric anemia	LINK
Urolithin A	Prostate, Lung, Colorectal, Kidney, Gastric, Glioblastoma, Melanoma, Myeloma, Gallbladder, Head and Neck	Typical commercial brands run at 500mg once or twice daily, with or without food, some brands suggest with meals	Trials eg in anti-aging science use the same dose range	LINK
Oat and Egg Functional Food	Breast, TNBC, Prostate, Lung, Colorectal, Kidney, Liver, Cervical, Pancreatic, Glioblastoma, Melanoma, Head and Neck, Gallbladder	Follow supplier guidance on dosage and use. https://shop.lantmannenfunctionalfoods.com/? Lowering tumor fluid pressure helps treatments work, start these before your treatment if possible. Use egg based salovum for short term "pulse" during therapy and oat products for sustained use over longer time periods	This trial in glioblastoma used 16g egg based Salovum four times daily. It discusses lowering that regime in follow on trials.	LINK
Coffee	Breast, Prostate, Colorectal, Liver, Non Melanoma Skin	Most dietary studies use standard 8oz servings as a guide. In many cases the findings are that benfits increase with intake. But in some cases such as prostate cancer there are important details in the PATHFINDER	No, but chlorogenic acid and, separately, green coffee extracts are used at 400mg and up to 2000mg
Flax	TNBC, Ovarian	Crushed flaxseed alone or in foods around 1/4 cup daily	Doses up to 50g daily in clinical trials for various diseases. Here a fairly typical 30g regime in inflammatory liver diseases	LINK
Propolis	Breast	Typical supplements range from 400 to 1000mg	Here 400mg x3 daily help recovery from radiotherapy	LINK
Walnuts	Prostate, Colorectal, Melanoma, Head and Neck	Dietary food item shown even at low useage to be helpful even at a few oz per week	Here, 2oz (56g) daily showed measurable activity in breast cancer	LINK
Mushroom	Prostate	Both dietary sources and many commercial supplements normally taken with food	In this example some patients saw responses between 8 and 14g daily of button mushroom extract	LINK
Zinc	Kidney, Ovarian, Cervical, Endometrial, Head and Neck, Non Melanoma Skin	Commercial supplements vary considerably . Moderate 20mg range generally advised	No
Intravenous HIgh Dose Vitamin C	Pancreatic, Glioblastoma	Commercial supplements vary. A moderate range around 20mg with food is generally accepted as safe.	Same as general guidance
Alpha Ketoglutarate	Melanoma, Kidney, TNBC, Non Hodgkin, Lymphoma	Typical usage is 1000mg daily with or without food, safety is good. Its especially important to ramp up and sustain your levels for maximum immunotherapy responses.	Larger doses of several grams have been safely used in various trials including here in bone disease at 6g daily	LINK
Horse Chestnut (Escin)	Thyroid	Common 300 to 600mg supplements contain 50 to 120mg of active compound, escin taken with food	Escin up to 150mg daily in vascular health. In oncology 0.6 mg/kg/day for 9 days, intravenous injection has been used, high absorption premium supplement would reacj this level	LINK

Impact	What	Why	Dose	Impact Summary	Activity in immunotherapy	Activity against lung metastatic sites?	Anti-metastatic in general	Higher dose before and during therapy?	Other comments
>50%	Lactoferrin	Large benefit to well balanced iron levels and higher hemoglobin, lower ferritin	10ml lipsomal LF daily, ideally on empty stomach	Yes in case studies 25% of patients had large response. Well functioning iron metabolism linked with 6X effect.	Higher circulating iron level almost 2X the response to this immunotherapy in kidney cancer. And Axitinib can deplete iron	Yes, about a 25% improved risk and 20% reduced side effects of chemotherapy	Low iron levels strongly linked to increased metastatic activity	Only with chemo. 1.5g lactoferrin twice daily 1.5 g for three 6-week cycles used in lung cancer	Hemoglobin over 110g/dL is reported with 2X effect vs lower. 130 to 150g/dL would be good. Low ferritin levels reduce progression risk from 60% to over 2X. LF helps with both
>50%	Sodium during immunotherapy	Boosts and activates immune response, enables strong anti tumor activity	With diet around 6-8g daily, need to be at 140-145mmol/l	Astonishing 9X higher response rate in patients with good 140mmol/l sodium (kidney cancer/nivolumab)	This is where sodium is an independent biomarker yes, active clinical trials still pending	Yes, regression of lung mets is part of Complete Response	Surprisingly, LOW sodium has growing evidence of increasing metastatic activity	This is not defined but up to 2/3 of patients during immunotherapy see low salt levels	There is a major risk that immunotherapy drugs lead to sodium deficiency after 4 to 5 weeks on therapy. So a higher intake is indicated
>50% during immunotherapy	Alpha Ketoglutarate (Ca-AKG)	Helps immunotherapy drugs overcome evasion	500mg x2 daily any time	Patients with high AKG levels have around 2X response rates	Evidence so for for PD-1 blockade for instance nivolumab and pembrolizumab	Yes, here also regression of lung mets is part of Complete Response	likely yes, there is lab evidence for this	YES Load up Ca-AKG before and during therapy	AKG may be lowered by metformin. This anti aging supplement has excellent safety
>50% (lower with chemo)	Vitamin D3	For immune system health and more	At least 10,000IU daily with meals	The evidence for benefit are most clear during immunotherapy, where impacts are substantial, around 2X	For immunotherapy in general, risk reduction around a half in patients from supplements. And protects thyroid	Yes regression of lung mets is part of increased response. And lung cancer themselves are similar affected	Yes	Research is into higher doses in order to increase the proportion of "responders"	Existing trials assessed 30ng/ml as sufficient. Other studies actively discuss supplementation to reach at least. 40ng/ml. Be sure to include magnesium and K2
>50%	Gut microbiota including Akkermansia	Indirect importance of gut bacteria is crucial in immunotherapy	Supplier dose, moderate level	Half the risk with TKI (inlyta) and good levels of akkermansia	Yes, in several cancers, a crucial influence on immunottherapy results	YES , 50 to 100% higher immunotherapy response with akkermansia	Indirectly yes	Yes, moderate supplements are a good idea	High fiber diet is the lead strategy, supplements with moderation
>50%	Red yeast rice or Atorvastatin	Anti-lipid and anti-inflammation. Possible combination with nattokinase	Per supplier or prescription, use premium brands	25% for average statin benefits with TKI (eg Inlyta) and maybe higher for atorvastatin	A remarkable 2X improved result in immunotherapy, risk reduction of 50%, including nivolumab	Yes, atorvastatin reported with a 59% improved risk level. Statin effects in general improve immunotherapy	Maybe	No	In lung cancer, combination with aspirin and metformin is reported to half relative risk levels
>50% (lower with chemo)	Zinc during immunotherapy	Essential for supporting immune response	Use high absorption brand, 20 to 40mg	25% for average statin benefits with TKI (eg Inlyta) and maybe higher for atorvastatin	2x improvement reported in other cancers, likely similar in kidney cancer	Yes the zinc trial is mainly for lung cancer indicating its relevance	Maybe	Slightly higher but in moderation	Current evidence shows strong effect in colorectal and lung cancer. Pending research in kidney cancer, a good addition
>50%	Inosine during immunotherapy	Immune cell activation increases	500 to 1500mg	Specific to immunotherapy, large benefit. But being explored elsewhere.	2x improvement reported in other cancers, likely similar here	Yes the first trial is mainly for lung cancer indicating its relevance	Maybe. A trial ongoing in breast cancer	Possibly	Current evidence shows strong effect in lung cancer. Pending research in kidney cancer, a good addition.
26-50%	Beta Glucans	Balance and help regenerate immune system, and reduce side effects	1 or 2x 250mg California Gold Immune Defense with Wellmune	Yes from some patient case studies in kidney cancer	Patented drugs pilot studies in other cancers having good effect	Indirect - there is improved immunotherapy response in lung tumors with beta glucans	Indirectly, lower NLR is linked to lower metastatic activity	As with astragalus	Continuous per supplier guidance
26-50%, at least	Desloratadine	Help immune system function and side effects	2 x 5mg daily	Example of 25% average risk reduction found	Currently reported in lung cancer	Indirectly - an 80% and much lower side effects (loratadine) in lung cancer immunotherapy	Probably	Only if advised	Loratadine is a possible alternative, some studies show higher effects in metastatic stages
26-50%	Selenium	Regulate immune system, anti inflammation. Helps onc drugs	200 mcg with meals	In high dose pilot study half of patients got 20 months "extra" time (Inlyta)	Strong in pre-clinical trials.	No research to date, pending further reports from clinical trial with pembrolizumab	Possible	YES dose TBD. Clinical trial at 2500 to 4000ug during therapy window (see Pathfinder)	Up to 4000ug is being trialed with axitinib or pembrolizumab (see also Supplement Library)
Up to 25%	Aspirin	Reduce blood clotting, currently not taking	-	Around 15% risk reductions reported	Improves response levels by up ro 47% and overall risk reduction 15%	Yes	Probably	Trials have used 160mg	Nattokinase+curcumin is a natrual anti-clotting and anti-metastatic
Up to 25%	Melatonin	Includes lab studies showing reduced immune evasion (PDL-1)	20mg evenings	Yes, 50% benefit with first generation immunotherapy	Evidence for first generation immunotherapy drugs, and in new lab studies	Yes, a 40% risk reduction also found at 20mg in evenings and improved side effects	Probably	20mg during therapy	There are pre-clinical mouse model studies showin compelling benefit for immunotherapy
Indirect-high	Astragalus	Re-balance immune inflammatory response (NLR marker)	500mg daily (50mg astragalaside)	Indirect evidence. Low NLR means 70 to 80% lower risk for progression	YES this effect is directly related to immunotherapy. NLR needs to be low and stay low	Halves progression risks in lung cancer alongside TKI treatment indicating probable effects in lung lesions	Yes, if lowering NLR, there is clear evidence	Normal dose except during therapy window when taking 2X
Indirect-high	Citrus Pectin/ PectaClear	Reduce copper and other metals, also help sugar metabolism	Started detox with Pectaclear at 2g x 2 daily on an empty stomach	Yes, lower levels are crucial. High copper levels are a major risk	Maybe	Yes, lower copper is better and effects are more than 50%	Quite likely	Hoping to clear any heavy metals before therapy starts	Be sure to maintain selenium and zinc levels during cleansing periods
Indirect-high	Functional egg and oat products	Reduce internal tumor fluid pressure, help treatment work	Supplier recommended dose	In this case the site is the lung	The clinical trials are new and not specific to immunotherapy	A 20% or higher effect for having lower fluid pressure during chemotherapy	Possibly yes, lower fluid pressure lowers metastatic potential of tumors	Anti-secretory Factor to lower inflammation especially in the intestines	Reduce gut inflammation, reduce tumor resistance, improve microbiome
26-50%	Treatment timing	AM vs PM matters		Yes a 43% benefit to morning treatment vs afternoon	Yes, for immunotherapy in metastatic kidney cancer		?		https://actionkidneycancer.org/how-time-of-day-of-immunotherapy-infusion-affects-kidney-cancer-outcomes/
	Other
>50%	Magnesium during immunotherapy								New evidence appearing supports this action in solid cancers.
Indirect-moderate	Walnuts and Urolithin A	Important for several effects, microbiome, fatty acid metabolism			High fiber diet can help immunotherapy. Increased response 14% decreased serious side effects by a quarter	https://www.asco.org/abstracts-presentations/ABSTRACT492494
Indirect-moderate	Berberine	Able to reduce both sugar related and fatty acid related cancer activity			Exercise has a positive impact of 15 to 27%	https://bjsm.bmj.com/content/59/10/715
Indirect-moderate	Curcumin	Anti-inflammatory activity. Also garlic and more funtional foods

Patients at higher risk of recurrence or metastatic progression post surgery may be treated with immunotherapy typically pembrolizumab (Keytruda). Those with metastatic disease may also be treated with dual immunotherapy usually ipilimumab/nivolumab (Yervoy/Opdivo) though either pembrolizumab or nivolumab with a tyrosine kinase inhibitor TKI such as axitinib (Inlyta) or cabozantinib (Cabometyx) is also common. The latter approach has some evidence for being more effective in lower risk patient groups here https://academic.oup.com/oncolo/article/28/2/157/6749534 and here for instance https://ascopubs.org/doi/10.1200/JCO.2023.41.6_suppl.646 TKIs are also commonly used in a second or third line of therapy.

Your PATHFINDER brings together research that help maximize the results of both immunotherapy or targeted drugs including TKIs. The IMPACTS tab summarizes these and can lead to Many more Good days by helping these treatments work, reducing your risk for progression and by easing drug side effects. If you are on immunotherapy, targeted drugs or both, you can continue to look for way to increase the results and reduce possible toxicities;

Be sure to fully read and absorb the PATHFINDER and its Impacts summary
If you have metastatic sites take a look into the corresponding Pathfinder for those too, for inspiration.
Use the Supplement Library Index and filter on and “Immunotherapy” and “Targeted Drugs” for ideas.
The Foods Library can complement your plan, including anti-metastatic strategies and metabolic health
In the Lifestyle section gathers fascinating evidence for diets and excercise
The PLANS section may have information from what others are doing and have learned

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