Fasting and Tumors

‫الصيام لتجنب آثار جلسات الكيماوي السيئة‬

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v=LGafhm1cuSI&ab_channel=USCLeonardDav
isSchoolofGerontology
Dr. Valter Longo - Fasting
Cycles Retard Growth of
Tumors
‫ ساعة قبلها‬72 ، 48 ، 24 ‫صيام‬
the longevity diet Dr. Valter Longo :‫له كتاب‬
2018
===================================
==========
31 ‫ مرجع‬Energy restriction and the risk of
spontaneous mammary tumors in mice- a meta‐
analysis:
All studies were published between 1942 and 1994.
The mean energy restriction in the 14 included studies was
37% (range 23–50%)
This means that in studies with more than 40% energy
restriction, 62% fewer animals in the intervention groups
developed spontaneous mammary tumors than in the
control groups.
In conclusion, this meta-analysis confirms that energy
restriction in itself consistently protects against the
development of spontaneous mammary tumor in mice,
irrespective of the type of restricted nutrient and/or other study
characteristics
====================
Incorporation of Fasting Therapy in an
Integrative Medicine
Ward: Evaluation of Outcome, Safety, and
Effects on Lifestyle
Adherence in a Large Prospective Cohort
Study 2005:
Fasting patients participated in a 7-day juice fast (intake
_350 kcal/day) with accompanying bowel cleansing, 2
prefasting relief days, and 3 days with stepwise
reintroduction of food.
 ‫العودة التدريجية للطعام الطبيعي‬
Bircher-Benner, and Mayr, medical fasting attracted a
growing number of patients from the 1950s on in Europe.4
Buchinger’s method of fasting included the free intake of
mineral water and the limited intake of fruit juice (350 ‫ى‬
kcal/day),6 which substantially reduces the protein loss of
gluconeogenesis.7,8
A fasting period of 7 days was defined to achieve optimal
feasibility. The fixed length of fasting allowed the
continuous forming of small patient “fasting-groups.” It was
anticipated that sharing the fasting experience within small
group would further support adherence to the program.
Fasting was preceded by two “relief” or prefasting days,
using a 800 kcal/day monodiet of fruit, rice, or potatoes
according to patients’ choices. Fasting then began the
following day with ingestion of an oral laxative, Natrium
sulfat (“Glauber’s salt” [Cesar & Loretz GmbH, Hilden,
Germany], 20–40g).
A fasting period of 7 days was defined to achieve optimal
feasibility. The fixed length of fasting allowed the
continuous forming of small patient “fasting-groups.” It was
anticipated that sharing the fasting experience within small
group would further support adherence to the program.
Fasting was preceded by two “relief” or prefasting days,
using a 800 kcal/day monodiet of fruit, rice, or potatoes
according to patients’ choices. Fasting then began the
following day with ingestion of an oral laxative, Natrium
sulfat (“Glauber’s salt” [Cesar & Loretz GmbH, Hilden,
Germany], 20–40g).
This was followed by stepwise reintroduction of food with
achievement of normocaloric intake by vegetarian meals on
the postfasting day 4.

One patient with gout experienced an symptomatic

increase in uric acid levels to 11.2 mg/dL and was treated
with allopurinol.
‫واحد عنده نقرس‬
Four patients experienced moderate gastric pain that
subsided after the rebuilding days
‫آالم معدة‬
‫ وجد أن الصيام آمن وال يصاحبه سوى أعراض طفيفة‬، ‫أيًضا‬
.‫من االنزعاج لعدد قليل من المرضى‬
:‫اآلثار الجانبية ونقص البروتين‬
However, some discomfort may be experienced during
fasting, especially on the fasting day 2 or 3, when
metabolism is changing to lipolysis. Typical com- plaints in
that context include tiredness, irritability, headache,
nausea, and light-headedness.6 These complaints, which
were perceived as nonsevere by all study patients in the
present and three previous studies,20,22,23 can be
successfully treated by self-help measures, which were
included in the prefasting patient informations in the current
study. The concern over fasting-induced loss of protein
reserves and related adverse effects is ever present in
nutritional medicine. However, the overall experience in
fasting therapy and the present results, which found
supervised fasting to be a safe approach, are in contrast to
these concerns.
========================
The effects of short-term fasting on tolerance to
(neo) adjuvant chemotherapy in HER2-negative
breast cancer patients: a randomized pilot study
2015
Even more importantly, the effects of short-term fasting
(STF) on susceptibility to chemotherapy differ between
healthy somatic and cancer cells, a phenomenon called
differential stress resistance (DSR) [10, 11, 13, 14]. In
healthy cells, nutrient deprivation shuts down pathways
promoting growth to invest energy in maintenance and
repair pathways that contribute to resistance to
chemotherapy [15, 16]. In contrast, tumor cells are unable
to activate this protective response due to uncontrolled
activation of growth pathways by oncogenic mutations.
Indeed, the persistently increased growth rate of tumor
cells requires abundant nutrients, and therefore, STF
renders tumor cells more sensitive to chemotherapy [10–
12]. Hence, STF is a promising strategy to enhance the
efficacy and tolerability of chemotherapy. In human
subjects, STF is safe and well tolerated [17–19].
:‫العالج‬
Drugs On the first day of each 3-weekly cycle (six in total),
women received TAC (docetaxel 75 mg/m2 IV for 1 h,
adriamycin 50 mg/m2 IV for 15 min and cyclophosphamide
500 mg/m2 IV for 1 h) with granulocyte-colony stimulating
factor (G-CSF; pegfilgrastim 6 mg) support the day after
chemotherapy administration.
Patients received prophylactic dexamethasone (8 mg, BID
the day before, the day of and the day after chemotherapy
administration) in order to prevent fluid retention and
hypersensitivity reactions. The anti-emetic agent
granisetron (serotonin 5-HT3 receptor antagonist; 1 mg)
was administered prior to chemotherapy infusion

STF had no beneficial effect on patientreported side effects

in this study. This may be explained by the large variability
of side effects between patients, which may be attributable
to occurrence of symptom clusters and pharmacogenomics
[35, 36]. This may have masked any beneficial effects of
STF.
Additionally, the relatively short period of fasting (48 h)
may explain the lack of benefit in terms of side effects:
previous studies have shown that a longer fasting period is
required to cause major changes in IGF-1 levels [20, 37].
Reduction of plasma IGF-1 levels is a critical mediator of
differential stress resistance in response to nutrient
restriction (see below) γ-H2AX phosphorylation indicates
the presence of double-strand DNA breaks and could serve
as a marker for chemotherapy toxicity in healthy cells, as
seen in a phase I/II trial with patients treated with
chemotherapy and belinostat [38].

We measured the induction of chemotherapy-induced DNA

damage in PBMCs by phosphorylation of H2AX (i.e. γ-
H2AX). The level of γ- H2AX in CD45 + CD3+ lymphocytes
was increased after 30 min in both groups. After 7 days, γ-
H2AX accumulation remained increased in the non-STF
group only, suggesting that STF promotes the recovery of
chemotherapy-induced DNA damage in these cells.

In CD45 + CD3- myeloid cells, the level of γ-H2AX was

increased after 30 min in the non-STF group, but not in the
STF group, suggesting STF protected these cells against
the induction of DNA damage by chemotherapy. As these
myeloid cells may harbor the antigenpresenting cells
required for induction of an effective anti-tumor immune
response, this result warrants further study [39]. Moreover,
the relation of this finding with the clinical benefit of STF still
needs to be established. The significantly higher
erythrocyte and thrombocyte counts observed after
chemotherapy in the STF group could be explained by
decreased breakdown of circulating cells and/or less
severe bone marrow suppression. This supports the
hypothesis that STF may protect against chemotherapy-
associated hematological toxicity.
:‫ضرر الديكساميثازون‬
Plasma glucose levels increased and insulin levels
remained constant in response to STF. The use of
dexamethasone may explain this phenomenon [40–42].
Dexamethasone was administered for anti-emesis,
reduction of fluid retention and dampening of
hypersensitivity reactions in response to docetaxel [43].
However, the metabolic effects of dexamethasone may
have attenuated the benefits of STF. In the absence of
dexamethasone, STF reduces circulating glucose, insulin
and IGF-1 levels [19, 44]. A decrease in IGF-1 affects other
factors (e.g. Akt, Ras and mammalian target of rapamycin
(mTOR)) to downregulate cell growth and proliferation [45–
47]. Reduction of IGF-1 is one of the key mediators of the
protective effects of STF in healthy cells [44]. Although
fasting modestly reduced plasma IGF-1 concentrations in
the current trial, the concomitant use of dexamethasone
probably attenuated the decline and thereby probably
counteracted the beneficial impact of the dietary
intervention.
Our study has some limitations. The most obvious limitation
of our study is the small sample size, which may have
limited the power of the study and precludes firm statistical
conclusions. Moreover, as high dose dexamethasone
induces insulin resistance, compensatory hyperinsulinemia
and hyperglycemia, its prophylactic use may have
counteracted the beneficial effects of STF. Therefore the
use of this drug warrants further study for future clinical
trials with STF.
Because it is likely that the positive effects of STF will be
enhanced if the period of fasting is prolonged [37, 49], a
very low calorie, low protein fasting mimicking diet (FMD) is
used to ease the burden of prolonged fasting [50].
Prophylactic dexamethasone will be omitted in the FMD
arm during the first 4 chemotherapy cycles to reduce its
potentially counteractive metabolic effects.
===========================
Fasting and fasting-mimicking diets for
chemotherapy
Augmentation 2020
Fasting-mimicking diets (FMDs) were developed to address
the safety concerns associated with PF, such as low rates
of compliance and malnourishment. FMDs— developed to
be a short-term intervention that is low in protein, high in
healthy fats, and containing complex carbohydrates, as well
as essential vitamins and minerals—mimic the effects of
fasting by decreasing insulin/glucose signaling pathway
activation, while avoiding the potential side effects of lack of
essential nutrients [32, 33].
The differences between IF and PF in mice include the
duration and/or frequency: IF cycles usually last up to 24 h
and are separated by 24 h of food intake (caloric intake
may be higher on the refeeding days to compensate for the
reduced calories on the fast days). PF instead lasts 2 or
more days and is followed by 1 week of normal food intake
to regain normal weight [4].
Additionally, and similar to other periodic fasting and
mealtiming interventions, the consumption periods between
the interventions can be modulated based on specific
nutrition requirements, for example, an increase in protein
intake to reduce the aging-associated loss of lean mass in
the elderly [37]. It is important to highlight that (i) an
increase in health span (induced by fasting or other anti-
aging interventions) does not always associate with
increased longevity [38] and (ii) it remains to be fully
established if increased longevity is associated with all
forms of fasting. Conversely, increased lifespan is not
always associated with increased health span or delayed
antiaging symptoms [39, 40].
CR only delays, but does not stop, the progression of
established cancers [69, 70].
The biggest concern is that chronic CR might not be
feasible for cancer patients receiving chemotherapy,
surgery, or immunity-based treatments, or who are at risk
for losing weight, as well as frail and/or cachectic patients,
because CR induces long-term weight loss, may delay
wound healing, and impairs immune function [2, 71–73].
To overcome the disadvantage of requiring long-term
interventions, various laboratories deployed variations of
fasting bouts. Unlike CR, the PF approach utilizes relatively
short (up to 4 days) periods of food restriction that can be
easily adopted to comply with existing chemotherapy
regimen and without chronic weight loss (since body weight
is usually regained during the refeeding period).
Additionally, due to the short time required to achieve the
desired metabolic effects which delay the incidence and
growth of cancer cells, fasting is expected to allow for
higher rates of adherence during the intervention period. A
3-day-long PF decreases blood glucose levels in mice by
up to 75% compared to the 15% reduction accomplished by
long-term CR or IF [4, 74]; considering the glucose
dependence of many malignant cells, this is an important
advantage of PF over CR or IF [75, 76]. In addition, the pro-
proliferative growth factor IGF-1 is reduced by up to 75%
following PF [77, 78], while CR causes a 25% IGF-1
reduction in mice [79] and only when CR is combined with
protein restriction are IGF-1 levels in humans reduced [68].

Despite these benefits, safety and compliance concerns

associated with PF (usually voiced by the treating medical
professionals) are limiting the use contribution of PF in the
clinic [4, 18, 23, 25–31].
‫ أيام على الصحة سلبيا‬5 ‫تراجع المراجع لتأثير الصيام‬
It is important that food intake after any PF cycle should be
initiated only after the half-life of potential carcinogens.
‫لم أفهمها‬
Thus, fasting prior to chemotherapy allows for the use of
higher doses of chemotherapeutic agents which may
increase treatment efficacy in otherwise hard-to-treat
situations. Examples of this may include advanced
metastatic tumors that are extremely difficult to cure once
tumor masses have spread to different organs or a change
in limitations of drugs that have a lifetime cumulative
dosage. For example, doxorubicin is limited to a cumulative
dose of < 550 mg/ m2 to reduce the risk of cardiotoxicity
[103].

‫ فإن الصيام قبل العالج الكيميائي يسمح باستخدام جرعات أعلى من عوامل‬، ‫وبالتالي‬
.‫العالج الكيميائي التي قد تزيد من فعالية العالج في المواقف التي يصعب عالجها‬
‫قد تشمل األمثلة على ذلك األورام النقيلية المتقدمة التي يصعب عالجها بمجرد‬
‫انتشار كتل الورم إلى أعضاء مختلفة أو تغيير في قيود األدوية التي لها جرعة‬
.‫تراكمية مدى الحياة‬
‫ مجم‬550 ‫ يقتصر دوكسوروبيسين على جرعة تراكمية أقل من‬، ‫على سبيل المثال‬
.]103[ ‫ لتقليل مخاطر السمية القلبية‬2 ‫ م‬/
In addition to the reduction in IGF-1 levels, serum glucose
levels also play an important role in the fasting-mediated
DSR effects and reducing glucose levels protecting mice
against chemotoxicity [104]. Yet drugs that promote
hyperglycemia, including dexamethasone and rapamycin,
are commonly administered to help with the management
of chemotherapy-related adverse effects in cancer patients
even though they have been shown to sensitize
cardiomyocytes and mice to doxorubicin [104]
In human mesothelioma and lung carcinoma cells, serum
starvation alone sensitizes to cisplatin treatment [116].
HepG2 and Huh-7 human hepatocellular carcinoma cell
lines show additive cytotoxic effects in both cell lines when
combining the kinase inhibitor sorafenib with fasting-like
conditions [117]. In vivo, water-only fasting cycles (lasting
48–72 h) can be as effective as chemotherapy in reducing
the progression of subcutaneous melanoma and breast
cancer models, whereas the combination of fasting with
chemotherapy improves treatment efficacy [114]. Fasting
combined with gemcitabine decreases pancreatic tumor
progression by ≥ 40%, partially by increasing gemcitabine
uptake [118]. Cisplatin in combination with fasting reduces
mesothelioma progression ≥ 60% compared to the control
and a complete remission is observed in 60% of the mice
treated with PF/cisplatin [116]. Forty-eight hours of water-
only fasting sensitizes mouse glioma models to radio- and
chemotherapy [115], an effect not observed by dietary
protein restriction alone [119]. Similarly, fasting when
combined with radiotherapy delays the growth of an
orthotopic KPC pancreatic tumor model after radiation and
increases the median survival to 43 days compared to 7
days in nonfasted, irradiated tumor-bearing mice [107].
Water-only fasting alone or when combined with oxaliplatin
has been shown to reduce the progression of the CT26
colorectal tumor [120].
Although for serum IGF-1 levels no clinically relevant risk
level has been established, several epidemiological studies
have associated IGF-1 levels ≥ 200 ng/ml with an increased
risk for various cancers [37, 135]. IGF-1 levels in subjects
with baseline levels ≥ 225 ng/ml were reduced nearly four
times more than the reduction observed in participants with
IGF-1 concentrations below 225 ng/ml [32].

Several clinical trials of FMDs in combination with

chemotherapy or with other types of active treatments are
currently ongoing at US and European hospitals, primarily
in patients who are diagnosed with breast cancer, with
single-arm clinical studies designed to assess the feasibility
and safety of the FMD or randomized clinical studies to
evaluate FMD effects on the toxicity of chemotherapy or on
the quality of life in patients undergoing chemotherapy

In a randomized crossover clinical trial of 34 patients with

breast or ovarian cancer, the FMD effects on the quality of
life and side effects in combination with chemotherapy
(including taxanes (docetaxel, paclitaxel), platinum agents
(carboplatin, cyclophosphamide), anthracyclines
(epirubicin, doxorubicin, methotrexatate, fluorouracil), the
IgG1 antibody bevacizumab, and pertuzumab or
trastuzumab for patients with HER2/ neu overexpression)
were assessed [132].

The FMD consisted of a daily caloric intake of < 400 kcal

primarily stemming from vegetable juice and small
standardized quantities of light vegetable broth starting 36–
48 h before the beginning of chemotherapy and lasting until
24 h after the end of chemotherapy.
The FMD prevented the chemotherapy-induced reduction
in quality of life without serious adverse events and it also
reduced fatigue.
The combination of periodic FMD and endocrine
therapeutics in 36 patients with hormone-receptor-positive/
HER2 breast cancer (clinical trials NCT03595540 and
NCT03340935) indicates promising results: 3 patients
treated in the second-line treatment setting received a total
of 10 (one patient) and 8 (two patients) FMD cycles.
Two of those patients demonstrated a clinically controlled
disease (at time of the data publication in July 2020),
whereas one of the patients that completed 8 FMD cycles
progressed after 11 months; the median progression-free
survival (PFS) in this clinical setting is 9 months [128]. In
these trials, the FMD lowered blood glucose, serum IGF-1,
leptin, and Cpeptide, while increasing circulating ketone
bodies, results that are in line with the mechanistic
understanding obtained from preclinical studies. In the
randomized, multi-center phase 2 “DIetary REstriction as
an Adjunct to Neoadjuvant ChemoTherapy for HER2
Negative Breast Cancer (DIRECT)” trial, 131 patients with
HER2-negative stage II/III breast cancer received either a
FMDor their regular diet for 3 days prior to and during
neoadjuvant chemotherapy [134