r.1964 PSA56 BxG.5+5 RPG.4+5pT2bN0LV1R0?>N1HT+RT>SRT>HT>SRT

[zosia bluszcz]

Gratulacje!

A swoja droga, to biedni ci zakwaszeni permanentnie, ryz konsumujacy Japonczycy

[kemoturf]

Gratulacje!

A swoja droga, to biedni ci zakwaszeni permanentnie, ryz konsumujacy Japonczycy

Tylko oni prawie nie jedzą mięsa ssaków, tylko ryby morskie z całym bogactwem kwasów nienasyconych i są narodem o niskiej umieralności na choroby krążenia i raka. A ryż brązowy, który je się w Japonii mniej zakwasza niż biały no i pewnie dochodzą jeszcze geny ryżożerców.

[andyfajka]

Tomek
Brawo także za wskaźnik markera.

Jędrek

[kemoturf]

Tym wynikiem muszę się pochwalić PSA 0.000 ng/ml

[armands]

Tym wynikiem muszę się pochwalić PSA 0.000 ng/ml

WOW!

No to ustawiłeś normę nie do pobicia.

Tomku gratuluję! Tak trzymaj

pozdrawiam
armands

[lui]

Tym wynikiem muszę się pochwalić PSA 0.000 ng/ml

Wspaniały wyniczek laboratorium które je wykonało, zapewnie dawno takiego nie widziało w swoich odczytach
Pozdrawiam lui

[andyfajka]

Tomek jest się z czego cieszyć gratuluję. 0,000 ale z mojej strony 100%
Dobrze dobrana terapia PO PIERWSZE ZERO
Odpowiednia i trafiona opieka medyczna PO DRUGIE ZERO
Aktywny z zasadami w leczeniu pacjent PO TRZECIE ZERO

Jędrek

[kate]

Witaj,

niby nic, zwyczajnie NIC, totalne ZERO........ a jak cieszy?
Tak trzymaj i nie chciej więcej .

Pozdrawiam
kate

[kemoturf]

Dzięki wszystkim za dobre słowa

Przejrzałem moją historię i widzę, że zabrakło jednego wpisu.
W lutym 2016 po nieznacznym wzroście PSA zafundowałem sobie 2 dożylne wlewy witaminy C, po 25g każdy.
Może tym strzałem trafiłem. Niedługo powtórzę tę operację.
Oczywiście utrzymuję wszystko to co pisałem wcześniej, czyli suplementację pro odpornościową, dietę nakierunkowaną na odkwaszanie.

[lui]

2 dożylne wlewy witaminy C, po 25g każdy.
[/b]Może tym strzałem trafiłem. Niedługo powtórzę tę operację.

Wiesz chyba rzeczywiście ma to u ciebie sens i przynosi efekty specjalne
Powiedz na marginesie jaki był koszt jednego wlewu z wit. C tam gdzie to wykonaleś.
Pozdrawiam raz jeszcze

[MAREK P.]

Super ustawiłeś sobie leczenie Tomek,gratulacje,
musisz koniecznie szczegółowo opisać
/co,jak i ile / w twoim przypadku bierzesz
jak wygląda twój dzień z życia

pzdr,M

[kemoturf]

Powiedz na marginesie jaki był koszt jednego wlewu z Wit. C tam gdzie to wykonaleś.

Pierwszą wit. C miałem podaną w klinice Imunomedica,u dr Szalusia w Warszawie.
Nie pamiętam dokładnie ceny, ale wziąłem też zestaw domowy, czyli wit. C, roztwór do rozcieńczenia i rurki, koszt tego, to trochę ponad 200 zł. Miałem w Poznaniu problem ze znalezieniem kogoś, kto to poda, bo nie ma na to procedur, ale udało się.
Znalazłem też w aptece w Niemczech koło Monachium za 20EU, ale 30 EU przesyłka, więc opłacałoby się kupić kilka np. 10 szt.
Cena roztworu i wężyków to około 20 zł., więc całość zamknęłaby się w 100 zł. Może w parę osób.

[lui]

Dzięki wielkie za wyczerpujące informacje. Temat jest już przybliżony i można rozważyć jego zastosowanie


Pozdrawiam ponownie

[jesien 2015]

Tym wynikiem muszę się pochwalić PSA 0.000 ng/ml

Gratulacje!! Chciałabym moc któregoś dnia napisać taki wynik PSA mojego męża! Pierwsze po zabiegowe PSA będzie na początku maja.

[bela71]

Piękny wynik! Gratulacje

[wlobo135]

Dołączam się do gratulacji kolegów. Nawet rak z Gleasonem 4+5 jest do pokonania.

[kemoturf]

Jeszcze raz dziękuję za udział w mojej radości.

Co do pokonywania raka, to jestem ostrożny, bo jeszcze tego nie widzę.
Póki co, wciąż jestem na HT, Zoladex od września 2014. Myślę, że zgodnie z tym co radzi urolog i z tym co czytałem pociągnę HT do 3 lat, a potem będzie generalne sprawdzenie. GS 4+5 to jednak rak wysokiego ryzyka. Najgorsze, że były przerzuty do węzłów i w obecnym stanie nie wiadomo nic więcej.

Marek pytał co robię. Wcześniej pisałem już w moim wątku, ale może zbiorę.
Poza HT korzystam z medycyny alternatywnej i wiedzy dr. Szalusia.

Suplementacja w kierunku wzmocnienia odporności organizmu.
- grzyby reishi zarodniki
- AHCC preparat z grzybów shitake
- witamiana D3 + K2
- lykopen preparat z pomidorów
- Selol, polski preparat selenowy
- Cynk
Dawkowanie co jakiś czas zmieniane.

W lutym miałem podaną dożylnie 2x witaminą C po 25g w odstępach tygodniowych (tylko uwaga nie kwas tylko sól Na, ascorbinian sodu, w razie czego służę informacjami) Od jakiegoś czasu już się do tego przymierzałem, bo sporo czytałem o dobrych efektach szczególnie przy raku prostaty, oczywiście nie jest to cudowny lek bo jednemu pomoże innemu nie, ale spróbować warto, bo nie obciąża organizmu.

Dieta w bezcukrowa kierunku odkwaszania organizmu, nie będę opisywał, bo można znaleźć dużo w necie. Generalnie dieta vegetariańska, z naciskiem na składniki alkalizujące, o niskim indeksie glikemicznym, bo cukier jest wszędzie, a rak za nim przepada. Dodatkowo jak dieta nie wystarcza piję Alkalę N lub sodę, aby mój organizm trochę zalkalizować. Badam PH moczu i na tej podstawie decyduję.

Co do dnia codziennego to cały czas normalnie pracuję we własnej firmie. Przez cały czas choroby miałem tylko 2 tyg zwolnienia, na czas w szpitalu i tydzień po RP. Staram się mieć dystans, aby się nie stresować. Rano spacer z psem. Po pracy bieganie, przynajmniej 3 razy w tygodniu (biegam od chyba już kilkunastu lat), w weekend nurkuję, codziennie minimum 1h gram na saksie i wsuwam warzywka. Robi się ciepło więc zacznę jeździć rowerem.

[MAREK P.]

Dzięki Tomek ,
jestem pewien że ta informacja dla jest dla
wszystkich ,zarówna przekonanych jak i nie do tych standardów
mało medycznych, do zastosowania lub nie w pomocy
leczenia , ja na pewno jestem za w/g słów -najważniejsze nie szkodzić

pozdrawiam przekonanych i tych nie ..też
Marek

[bela71]

Dobre wibracje z saksofonu, o, to jest to!

[zosia bluszcz]

Dieta w bezcukrowa kierunku odkwaszania organizmu, nie będę opisywał, bo można znaleźć dużo w necie. Generalnie dieta vegetariańska, z naciskiem na składniki alkalizujące, o niskim indeksie glikemicznym, bo cukier jest wszędzie, a rak za nim przepada. Dodatkowo jak dieta nie wystarcza piję Alkalę N lub sodę, aby mój organizm trochę zalkalizować. Badam PH moczu i na tej podstawie decyduję.

Tomek,

Przeczytaj moze, co napisalam Kangurowi na temat zakwaszania i odkwaszania organizmu (post zacytowany nizej).
Picie sody moze ci najwyzej, chwilowo, zmienic pH sokow zolądkowych.
Mam nadzieje, ze te nienaukowe teorie, ktorym chylisz czola, nie pochodza od Twojego ulubionego doktora Sz. ...

pzdr
zosia

autor: zosia bluszcz » 22 mar 2016, 14:39

Kangur pisze:
Zastanawiam się jeszcze nad wpływem zakwaszenia organizmu, a rozwojem komórek nowotworowych? czy moze ktoś dysponuje wiedzą na ten temat?

Jakiego "zakwaszenia organizmu"?
Skad masz wiedziec czy Twoj organizm jest "zakwaszony"?
Jezeli Twoja odpowiedz brzmi - badajac pH moczu - jestes w błędzie. Mocz nie jest wskaznikiem pH calego organizmu.

Organizm czlowieka, to zepol naczyn polaczonych, ktory moze prawidlowo funkcjonowac gdy jego pH wynosi 7.4 i Twoj organizm automatycznie koryguje wszelkie odchylenia od tej wartosci. Spadek pH ponizej 7 lub wzrost powyzej 7.7 to niechybna smierc.
Rzeczywiscie kwasnie jest jedynie srodowisko Twojego żołądka (pH 3) abys mogl prawidlowo trawic dostarczany pokarm.


Polecam lekturę:

Your Urine is Not a Window to Your Body: pH Balancing – A Failed Hypothesis | Science-Based Pharmacy
https://sciencebasedpharmacy.wordpress. ... ypothesis/

[ewaryn]

To może warto przeczytać to:
DMSO i wodorowęglan sodu w leczeniu opornego bólu nowotworowego:
http://www.ncbi.nlm.nih.gov/pubmed/21426213
Są jeszcze inne ciekawe pozycje:
http://www.ncbi.nlm.nih.gov/pubmed/19276390
http://www.ncbi.nlm.nih.gov/pubmed/21663677
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722989/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834485/
To nie jest prawda, że wodorowęglan sodu podnosi PH tylko w żołądku.
Sprawdziłam osobiście:
zmierzyłam PH moczu przed zażyciem roztworu wodorowęglanu sody w wodzie. I po ok. 30-40 minutach po. PH moczu z 6,8 podniosło się na 7,6.
To był tylko eksperyment. Nic mi się nie stało:)
Jednak w ostatnim czasie ocierałam się o artykuły, w których pisano że zbyt długie alkalizowanie organizmu niekoniecznie jest korzystne.

[MAREK P.]

ZosiaB jak zwykle pesymistyczna
pewnie dlatego że u nich już jesień

[kemoturf]

Widzę, że jak zwykle wywołałem burzę.
Ja wiem swoje. Zmienił się diametralnie mój komfort życia, nie wiem czy za sprawą wit D3, czy za sprawą diety i alkalizacji, czy pozostałej suplementacji. Budzę się rano wypoczęty, czuję się znakomicie, mam pełno energii i pozytywnego spojrzenia na świat. Moja bardzo silna alergia na różnego typu zielsko, a szczególnie bylicę, praktycznie zniknęła itd. Wcześniej pomimo dobrego statusu życiowego żyłem na krawędzi depresji, ciągle przemęczony.

Wiem też z własnych obserwacji, że soda zmienia pH moczu, nie tylko pH żołądka. Skoro jest w moczu, to przeszła przez jelita i przez krew. Niewydalona część wodorotlenku wpływa też na ph krwi i całego organizmu. Kontroluję ph moczu i widać to czarno na białym. Z drugiej strony moim celem nie jest zażeranie sody, a bardziej dieta alkalizująca i utrzymywanie tą metodą wysokiego pH.

Co do nienaukowości pewnych metod to uważam, że to określenie nie jest trafne, bo są one badane przez różne zespoły naukowe i są dostępne opracowania naukowe w tych sprawach. To są metody nieprzyjęte przez główny kanon medycyny akademickiej. Różne są teorie, dlaczego, ale chyba nie ma sensu o tym dyskutować.
Ja będę nadal robił swoje bo widzę, że to dobra droga. Nie chcę nikogo przekonywać, bo każdy powinien mieć swój sposób leczenia, w który wierzy, bo wiara w wyzdrowienie to ponad połowa sukcesu w leczeniu. A ja zakładam, że pozbędę się raka definitywnie! Marek prosił o opisanie tego co robię, więc napisałem.

http://www.ncbi.nlm.nih.gov/pubmed/18042305

[iwas]

Gratuluję wyniku i wytrwałości w postanowieniach

Z ciekawością (i nie tylko) śledzę Twoją historię i te dodatkowe informacje, o których piszesz, są bardzo cenne dla wielu osób. Bo przecież chyba większość z nas nie skupia się tylko i wyłącznie na zaleceniach lekarskich (leczenie)- zastanawiamy się co trzeba, co można a czego nie powinno się robić, żeby wspomóc leczenie ale nie zaszkodzić.

Z całą pewnością dieta zakwaszająca (mięso, cukier) nie jest zdrowa (a taką mamy słabość), nawet dla tych osób, które nie chorują (jeszcze). Ruch, wzmocnienie odporności, dieta, odstresowanie - to wszystko wpływa na lepsze efekty leczenia. I choć większość lekarzy nie przywiązuje wagi lub po prostu nie mówi, czy nie wskazuje określonego właściwego "stylu życia", to nie znaczy, że nie należy tego robić, tym bardziej że efekty są "do pozazdroszczenia". Co do sody nie mam zdania, więc się nie wypowiadam. Najważniejsze - nie szkodzić sobie.

Pozdrawiam serdecznie
Iwona

[zosia bluszcz]

Tomek, z Twojego linku nic nie wynika, poza tym, ze pH sikow zmienia sie w zaleznosci od diety, ale to zadna nowosc.
Jezeli uwazasz, ze robiąc to, co robisz czujesz sie lepiej - kontynuuj sikanie na pasek, picie sody oczyszczonej oraz wlewy z witaminy C, model DIY (pisales, ze nabyles jakis zestaw rurek do wlewow?).

Jezeli masz dostep do powaznych opracowan naukowych na temat "odkwaszania" organizmu podaj linki, z gory dziekuje, chetnie przeczytam.


Poza tym,
Pani Ewaryn wrzuca po raz kolejny listy linkow, z ktorych zwartoscia sie nie zapoznala.
Badania dotyczyly raka piersi glownie i byly prowadzone na myszach i liniach komorek.

Zas pan MarekP usiluje byc zlosliwy, ale mu to kiepsko wychodzi.

Pozdrawiem jesiennie i optymistycznie z miejsca, gdzie slonce swieci przez 300 dni w roku.

zosia

[rowerzysta]

...Z całą pewnością dieta zakwaszająca (mięso, cukier) nie jest zdrowa (a taką mamy słabość), nawet dla tych osób, które nie chorują (jeszcze). Ruch, wzmocnienie odporności, dieta, odstresowanie - to wszystko wpływa na lepsze efekty leczenia....
Iwona

Nic dodać nic ująć tak trzymać

[rowerzysta]

.... Zas pan MarekP usiluje byc zlosliwy, ale mu to kiepsko wychodzi....

zosia

Przesadzasz! On tylko che mieć najwięcej postów z Was wszystkich co nie jest złe dla oglądalności ale ze szkodą dla poziomu forum
pozdrawiam rowerzysta

[diego]

Zawsze doceniałam osoby dbające o dietę i swoje zdrowie, ale soda, to różnie bywa, ja po kilku dniach stosowania sody dostałam bardzo wysokiego ciśnienia i ustabilizowanie trwało aż 20 dni
Pomogła zmiana leków i odstawienie sody.
Życzę wiary w zdrowe odżywianie i wspaniałych wyników
pozdrawiam

[zosia bluszcz]

Zawsze doceniałam osoby dbające o dietę i swoje zdrowie, ale soda to różnie bywa ja po kilku dniach stosowania sody dostałam bardzo wysokiego ciśnienia i ustabilizowanie trwało aż 20 dni
Pomogła zmiana leków i odstawienie sody

AMEN

[MAREK P.]

.... Zas pan MarekP usiluje byc zlosliwy, ale mu to kiepsko wychodzi....

zosia

Przesadzasz! On tylko che mieć najwięcej postów z Was wszystkich co nie jest złe dla oglądalności ale ze szkodą dla poziomu forum
pozdrawiam rowerzysta

no to mi się dostało ,
ZoziuB pisałem to żartobliwie jeśli dotknęło Cię to ...sorry ,
i do rowerzysty nie wiem w którym miejscu zaniżyłem poziom forum kolego
jeśli czytasz moje posty /w co wątpię/to powinieneś znać mój styl

A M E N

[kemoturf]

Odebrałam też wynik D3 25(OH) 53 ng/ml przy suplementacji 4000jm dziennie. Na lato, zmniejszę dawkę.

[armands]

Odebrałam też wynik D3 25(OH) 53 ng/ml przy suplementacji 4000jm dziennie. Na lato, zmniejszę dawkę.

Możesz, ale nie musisz. Do poziomu toksycznego w naszych warunkach pogodowych raczej nie dobijesz.

Pozdrawiam
armands

[ed1954]

kemoturf,

z takimi wynikami niechybnie i nieuchronnie zmierzasz w kierunku nieoznaczalności PSA, czyli w ślady forumowicza aannddy.

Czego Ci serdecznie życzę!

Z pozdrowieniami,
syn.

[kemoturf]

Kolejny wpis z pamiętnika młodego symulanta
PSA 0,000 ng/ml
Cały czas utrzymuję suplementy i HT, o których pisałem wcześniej.
W kwietniu zrobiłem 4 dożylne wlewy witaminy C, raz w tygodniu 25g (ascorbinianu sodu) w wodzie.
To już kolejna porcja vit C. Pierwsza była w lutym 20016, 2x po 25g, raz w tygodniu.
Po tej pierwszej dawce PSA spadło do 0.000.

[jesien 2015]

Gratuluje wyniku!
Uniwersytecki Szpital w Herlev ( Dania), w którym leczony jest mój mąż, prowadził badania kliniczne nad zastosowaniem witaminy C w leczeniu raka. Niestety nie mogę doszukać się wyników. Nabor został zamknięty już dawno, badania zakończone, powinna gdzieś być publikacja. Jeśli nie znajdę wyników, mąż zapyta o nie swojego urologa w czerwcu przy kolejnej wizycie.
https://clinicaltrials.gov/show/NCT01080352

[kemoturf]

Z pewnością takie badania byłby ciekawe. Koniecznie zapytaj. Spróbuję też poszukać w materiałach tego uniwersytetu. Ważne jest jacy chorzy byli brani do badań, czy byli leczeni czymś jeszcze, w jakim stadium choroby itd. W necie trochę rzetelnych informacji jest, ale w większości to opowieści.
Wiem tylko tyle, że u mnie jest bezpośrednia korelacja czasowa pomiędzy podawaniem vit C a spadkiem PSA.

[nadzieja81]

kemoturf dzisiaj dopiero przeczytałam Twoją historię i tylko upewniasz mnie w tym że leczenie akademickie poparte naturalnym i odpowiednią suplementacją działa cuda. Super cieszę się ! Tylko trzeba chcieć i być otwartym ... Mój tato nie chce "współpracować'
Nie mam już siły tłumaczyć swoim bliskim że takie działania znacznie by im pomogły... Trzeba samemu tylko chcieć. Mam na myśli tu swojego męża z SM i tatę.

[kemoturf]

Ponoć 3/4 uzdrowienia zależy od nas samych, reszta to leki. Ale trzeba chcieć sobie pomóc. Jestem daleki od radzenia komuś rezygnacji z osiągnięć medycyny, ale w niektórych przypadkach trzeba rozsądnie rozważyć pewne sprawy i zdecydować czy nie spróbować zrobić czegoś lepiej. Jak widzisz konsekwentnie trzymam się pewnej linii leczenia i efekty są póki co świetne. Jestem daleki od hurra optymizmu, bo główne sprawdzenie nastąpi po odstawieniu Zoladexu. Wczoraj dostałem kolejny zastrzyk, jeszcze mnie boli brzuch i jak nic się niepokojącego nie wydarzy, będą jeszcze 2, czyli koniec HT luty 2017, już o tym marzę. Łącznie to będzie 2.5 roku HT i zobaczymy. W końcu trzeba kiedyś powiedzieć sprawdzam.
Może niech Twoi Panowie przeczytają moją historię na forum. Ona jest w pełni prawdziwa.
Też nie wszystko na wszystkich musi działać, ale spróbować warto.
W razie czego służę pomocą i dodatkowymi informacjami.

[MAREK P.]

Tomek super super super
ale tak lekko nie będzie i
będziesz musiał pewnie wydać książkę-instrukcję



-Moja szczęśliwa historia walki z RGK

pzdr.M

[zosia bluszcz]

No to masz trochę lektury



Review of high-dose intravenous vitamin C as an anticancer agent

Michelle K WILSON, 1 * Bruce C BAGULEY, 2 Clare WALL, 2 Michael B JAMESON 3 and Michael P FINDLAY 2 1 Auckland City Hospital, 2 University of Auckland, Auckland and 3 Waikato Hospital, Hamilton, New Zealand


Abstract

In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid).
These studies were criticized for their retrospective nature and lack of standardization of key prognostic factors including performance status.
Subsequently, several well-designed randomized controlled trials failed to demonstrate a significant survival benefit, although these trials usedhigh-dose oral vitamin C.
Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant but may have pro-oxidant activity at high concentrations. The mechanism of its pro-oxidant action is not fully understood, and both intra- and extracellular mechanisms that generate hydrogen peroxide have been proposed.
It remains to be proven whether vitamin C-induced reactive oxygen species occur in vivo and, if so, whether this will translate to a clinical benefit.
Current clinical evidence for a therapeutic effect of high-dose IV vitamin C is ambiguous, being based on case series.
The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response.
The methodology exists to determine if there is a role for high-dose IV vitamin Cin the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this challenging.
Currently, the use of high-dose IV vitamin C cannot be recommended outside of a clinical trial.


INTRODUCTION
Vitamin C is an essential micronutrient for humans, who lack the enzyme required for its synthesis. Vitamin C is well known for its antioxidant activity although it is only one of a large variety of dietary antioxidants.
In the 1950s, vitamin C was originally hypothesized to be protective against cancer, 1,2 but in the 1970s, Ewan Cameron and Linus Pauling suggested that it also had a therapeutic effect, reporting increased survival of patients with advanced cancer following high-dose IV vitamin C treatment. 3

In contrast, several subsequent randomized controlled trials (RCTs) of high-dose oral vitamin Cfailed to demonstrate a similar benefits, 4–6
opening the issue of therapeutic effectiveness to controversy.
More recent studies showed that high plasma concentrations of vitamin C can only be achieved if vitamin C is administered intravenously or intraperitoneally as the rate of absorption from the gut is limited with oral administration. 7,8
Plasma concentrations in humans following high-dose IV vitamin C are approximately 200 times higher than those achieved following oral administration. 8
High-dose oral and high-dose IV vitamin C treatment therefore have to be considered as distinct therapeutic approaches.

The purpose of this review is to survey the literature to analyze the antitumor effects of vitamin C in both human and animal studies in terms of the dose and achieved plasma vitamin C concentrations. In analyzing the effects of vitamin C in rodent models, it must be noted that rodents synthesize their own vitamin C and therapeutic effects are limited to “high plasma vitamin C.”


The five questions this review will address are therefore
(i) Does vitamin C (at high plasma concentrations) have antitumor activity in rodent systems?
(ii) If so, how does vitamin C potentially exert its antitumor activity?
(iii) Does vitamin C (at high plasma concentrations) have clinical antitumor activity?
(iv) Is vitamin C safe alone and in conjunction with chemotherapy? and
(v) If the answer is not clear, how can the issue of therapeutic efficacy be addressed in the future?


DOES VITAMIN C (AT HIGH PLASMA CONCENTRATIONS) HAVE ANTITUMOR ACTIVITY IN RODENT SYSTEMS?
Despite a large amount of preclinical in vitro data on the effects of vitamin C on tumor cells, there are few reports on the antitumor activity of high-dose vitamin C in xenografts of human tumors in immunodeficient mice, a well-characterized method of predicting potential anti- tumor activity in humans (Appendix I).
Chen et al. demonstrated that vitamin C (4 g/kg intraperitoneal [IP] once or twice daily) reduced tumor growth and weight by 41–53% using ovarian (Ovcar5), pancreatic (PAN01) and glioblastoma (9 L) tumor cell lines in mice. 9
The effective plasma concentration that decreased survival by 50% (EC 50 ) was less than 10 mM in 75% of the tumor cells tested, but in contrast cytotoxicity was not evident in normal cells at ascorbate concentrations exceeding 20 mM.
The lack of any complete response led them to propose that the role for vitamin C may be as an adjunct alongside chemotherapy.
Similar results have been shown in mesothelioma cell lines. 10
In keeping with this premise, Espey et al. demonstrated that vitamin C (4 g/kg) inhibited the growth rate of PAN02 pancreatic tumors by approximately 40%, and also augmented the effect of concurrently administered gemcit- abine (30 mg/kg). 11
This dose of vitamin C in rodents is equivalent to 1.5 g/kg in humans. 12

HOW DOES VITAMIN C POTENTIALLY EXERT ITS ANTITUMOR ACTIVITY?
One of the issues with the use of high-dose IV vitamin C is the lack of understanding of its potential mechanismof action. Although initial theories centered on modification of biological responses, more recent research has concentrated on the importance of both extracellular and intracellular effects of vitamin C. McCormick postulated that vitamin C protected against cancer by increasing collagen synthesis. 1
Cameron and Pauling later hypothesized that the association between vitamin C and hyaluronidase activity was key.
They speculated that a high intake of vitamin C increased the biosynthesis of a physiological inhibitor of hyaluronidase (PHI) and subsequently reduced the invasiveness of proliferative disease. 13
Experimental studies, while demonstrating that scorbutic guinea pigs have higher levels of PHI compared with those receiving oral vitamin C, failed to show a link between PHI levels and the amount of vitamin C given. 14
High-dose oral vitamin C has been shown to be a potent immunomodulator, enhancing the activity of natural killer (NK) cells in vivo. 15
NK cells are thought to be important in immune surveillance, preventing growth and dissemination of tumor cells. 16
Heuser and Vojdani demonstrated that vitamin C caused an increase not only in NK activity but also B- and T-cell activity in patients previously exposed to a toxic chemical. 17
Both these studies used oral vitamin C.

Other studies have found evidence to the contrary so while it is a potential mechanism, this remains unproven. 18

Extracellular mechanisms for vitamin C action Studies by Chen et al. established that high doses of vitamin C in mice (IV or IP) generated significant extra- cellular concentrations of hydrogen peroxide (H 2 0 2 ). 19
H 2 0 2 is central to a diverse range of physiological responses pivotal to disease progression, including angiogenesis, and oxidative stress. 20
They hypothesized that the presence of a catalyst such as ferric ion within the extracellular matrix of tumors could oxidize vitamin C to ascorbate radicals, which then could then donate electrons to oxygen to form superoxide radicals (O 2 − ) (Fig. 1).
This would be converted by superoxide dismutase to the potentially tumoricidal peroxide ion. 19
Because peroxide is rapidly converted to oxygen in blood, the accumulation of peroxide would occur only in tissues.
The identity of the catalyst was not elucidated but a later study suggested that it could be the metalloprotein ferritin, which is secreted by some tumor cells. 22

Extracellular peroxide, depending on concentration, can have a cytotoxic effect.
Chen et al. demonstrated that high (pharmacologic) but not low (physiological) concentrations of vitamin C killed cancer but not normal cells, with cell death dependent on extracellular vitamin C concentrations. 9,19,23
H 2 0 2 generation displayed a linear relationship with the formation of the vitamin C radical. 23
The pattern of cell death changed from apoptosis to pyknosis/necrosis as vitamin C concentrations increased, in keeping with H 2 0 2 -mediated cell death. 23
When H 2 0 2 scavengers were employed they were protective against cell death. 23
H 2 0 2 generated by vitamin C oxidation and exogenously added H 2 0 2 produced cell death curves that were indistinguishable. 23
Chen et al. did not demonstrate a lower level of antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) in malignant cells to explain the selective death of cancer cells. 23
Instead they theorized that H 2 0 2 diffuses into sensitive cancer cells and causes toxicity by adenosine triphosphate (ATP) depletion. 19
The selective cancer cell death may be explained by the different mechanisms of ATP generation with cancer cells primarily using anaerobic generation and normal cells aerobic generation. It remains uncertain whether this in vitro and in vivo data will translate into clinical benefit.

Intracellular mechanisms for vitamin C action
Vitamin C is taken into cells by sodium-dependent vitamin C transporter 1 (SVCT1) and SVCT2 sodium- dependent transporters that are members of the SLC23 family. 24
The oxidized form of vitamin C, dehydroascorbate, can also be taken up by the glucose transporter (GLUT) and reduced in the cell to ascorbate. 25
Macrophages and vascular endothelial cells can express high levels of SCVT2 and thus concentrate vitamin C to a high millimolar degree. 26,27
High intracellular vitamin C concentrations are proposed to inhibit hypoxia-inducible factor (HIF)-1α activation. HIF plays an important role in determining patterns of gene expression in cancer and is another potential target of vitamin C action. HIF-1α is broken down by hydroxylases, which require iron and ascorbic acid as cofactors. 28
Vitamin C deficiency has been shown in vitro to compromise hydroxylation of HIF and upregu- late HIF-1α. 29,30 HIF-1α overexpression promotes tumor progression through angiogenesis, confers resistance to chemotherapy and radiotherapy, and carries a poor prognosis. 29,31,32
Vitamin C levels have been studied in patients with endometrial cancer, demonstrating significantly lower levels of vitamin C in high-grade tumors compared with paired normal tissue. 33
Markers of HIF-1 activation (HIF-1α protein, GLUT-I and BCL 2/adenovirus E1B) were elevated in samples with low vitamin C levels, in keeping with the theory that low tissue vitamin C concentrations upregulate the HIF-1 pathway.

There was also an inverse correlation between vascular endothelial growth factor levels and vitamin C concentrations. Similar findings have been demonstrated in gliomas. 32
Genetic approaches and small-molecule inhibitors targeting HIF-1 have proven effective at decreasing resistance to chemotherapeutics in a number of different cancers. 34,35
A study using vitamin C with a recombinant adenovirus-associated virus (rAAV) vector bearing small-interfering RNA targeting HIF-1α (rAAV-siHIF) in pancreatic tumors in athymic mice found that vitamin C could inhibit expression of HIF-1α protein but not messenger RNA expression. 36
It inhibited the growth in early and middle stages of disease but not advanced Neutrophil Superoxide dismutase Metalloprotein complex Extracellular ascorbate NADPH oxidase BH4 O2 O2˙¯ O2 O2˙¯ e¯ H2O2 H2O2

Figure 1
Extracellular mechanism of action of high-dose intravenous vitamin C.

Legend: Two possible mechanisms for the generation of extracellular hydrogen peroxide (H 2 O 2 ) in response to ascorbate.
In the first, as shown on the left-hand side, molecular oxygen is reduced to superoxide by a molecular complex of ascorbate and an as yet uncharacterized metallo- protein catalyst (such as ferritin). 9
In the second, as shown on the right-hand side, ascorbate is first taken up by a cell such as a neutrophil, either directly by an ascorbate transporter or indirectly as dehydroascorbate by the glucose transporter. Here it stabilizes tetrahydrobiopterin (BH 4 ), preventing its degradation and leading to activation of the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which reduces molecular oxygen to superoxide. 21 In each case, peroxide is generated subsequently by the enzyme superoxide dismutase. 24

The lack of blood supply in advanced stages is thought to compromise the delivery of vitamin C to the tumor. 36

DOES VITAMIN C (AT HIGH PLASMA CONCENTRATIONS) HAVE CLINICAL ANTITUMOR ACTIVITY?
In 1974 Cameron and Campbell published the first clinical trial suggesting the therapeutic role for vitamin C in cancer. 37
Fifty patients with no further conventional treatment options were treated with IV and oral vitamin C (20% receiving oral only).
Of five tumor regressions described, one occurred in a patient with ovarian cancer who had extensive pelvic disease at initial diagnostic laparotomy, which was not present at autopsy. However, this did not seem to prolong survival with the patient dying on day 33.
Two other patients reported to have regression had no histological diagnoses of incurable disease. One of these patients diagnosed with advanced pancreatic cancer at laparotomy was found to have chronic pancreatitis on autopsy.
A further patient with lymphoma had evidence of remission while on vitamin C, which recurred once treatment stopped. Remission was again achieved on restarting vitamin C. 38
Another 48% of patients reported a subjective improvement quantified by a reduction in analgesic use and need for paracentesis. 37
However, with no control group, a placebo effect for these symptomatic improvements cannot be excluded.
Cameron and Pauling then published two historically controlled trials, each comparing 100 patients treated with high-dose vitamin C, with 1000 controls matched by age, sex, tumor site and histological features (Fig. 2). 3,39
Both trials found a significant prolongation of mean survival (210 vs 50 days and 293 vs 39 days, respectively). 3,39
However, neither of these trials was standardized by two critical prognostic factors: performance status and stage. 4,40
The consistency of determination of “untreatability” is also controversial in the initial trial: 20% of the control group died within a few days of being deemed untreatable compared with none.

(...) The Mayo Clinic conducted three RCTs to examine the efficacy of vitamin C (Fig. 2), none of which showed a definitive benefit in terms of survival or quality of life. 4–6
They compared 10 g of vitamin C administered orally versus placebo.
The initial trial used patients unsuitable for further systemic therapy either because of progression during treatment or because their general condition precluded further treatment. 4
These negative results were refuted due to concerns that, if vitamin C acts by improving host resistance, prior treatment would obscure any benefit. 41,42
All but nine patients had had previous treatment compared with only 4 of the 100 patients in the initial Cameron and Pauling trial. 42

The second RCT was conducted in 100 cytotoxic naive patients with colorectal cancer. 5
None of the 38 patients with measurable disease demonstrated disease response. 5
This trial was criticized as it was limited to patients with colorectal cancer and it was questioned whether negative results in this tumor group were transferable to other primary sites. 5,40
However, 20% of the patients in the initial Cameron and Pauling trial had colorectal cancer and they demonstrated similar survival benefit to other tumor subtypes. 3,39

Subsequently, 144 patients with predominantly lung and colorectal primaries were studied. They described an initial benefit in overall wellbeing but this was lost by 6 weeks. 6
The results from these RCTs led to the current opinion among oncologists that high-dose vitamin C is ineffective.

However, it is now recognized that vitamin C pharmacokinetics differ significantly with oral and IV dosing. 8
Plasma vitamin C concentrations were not measured in any of these trials.

Around this time two further trials published similar results to the historical trials, demonstrating prolongation of survival times and improvement in quality of life (Fig. 2). 43,44

Cameron and Campbell published the only trial that measured plasma levels in association with survival time and demonstrated a linear relationship between dose and IV plasma vitamin C levels. 43
Levels above 3 mg/dL (0.17 mM) were reported as desirable but this concentration based on recent literature appears too low to exert a pro-oxidant effect. 43
Treatment was not randomized and was dependent on clinician preference, creating the potential for selection bias. Again there was no stratification by performance status.

Since this time case series and reports have continued to raise interest in a therapeutic role for high-dose Vitamin C, but there has been limited correlation with plasma vitamin C concentrations. 38,45–49

Riordan et al. and Padayatty et al. published the largest of these series with seven 45
and three patients, respectively. 46
These series cover a spectrum of malignancies but there is significant overlap, with many of these cases published repeatedly. 37,38,45–47

Padayatty et al. reported on three patients with renal cell cancer(RCC), non-Hodgkin lymphoma (NHL) and bladder cancer, in keeping with the guidelines of the US National Cancer Institute Best Case Series Program. 46
Two of these patients were also included in the Riordan series et al. 45
All of these patients used IV vitamin C either with standard therapy or alongside other alternative therapies, making it impossible to definitively assign clinical benefit to vitamin C.
They described positive results with either improved health status or slowed disease progression but with no control group this is inconclusive. RCC is a malignancy that has a variable natural history and one that rarely can undergo spontaneous regression (although usually following nephrectomy, which was not the case in this report). 50
The latter two cases reported received standard therapy with radiation and surgery, respectively. All of these cases had the slim potential for long-term remission with these therapies. 51
Interestingly, the case of NHL did have nodal relapse confirmed histologically that appeared to regress with vitamin C.
There were no plasma vitamin C concentrations measured to help establish a dose–response relationship.
There was often a lack of histological diagnosis in the case of recurrent or metastatic disease.

In view of these factors, they do not provide definitive evidence of a beneficial or detrimental role for IV vitamin C.

Drisko et al. published a case series of two patients with advanced stage IIIc ovarian cancer treated with chemotherapy and IV vitamin C (60 g twice weekly). 49
Both these patients had optimal surgical debulking, a key prognostic determinant of patient outcome. 52
These patients were reported to demonstrate prolonged survival with both patients alive over 3 years out from diagnosis.
Treated stage IIIc ovarian cancer has a 5-year survival rate of around 30%. 53
The survival for these patients consequently may be explained by optimal conventional therapy. However, neither of these patients had subsequent chemotherapy over this time.

A recent retrospective multicenter epidemiological cohort study examined the effect of IV vitamin C (7.5 g weekly) on quality of life during adjuvant chemotherapy and radiotherapy and aftercare in patients with breast 2
Mean intensity scores in patients treated with vitamin C during adjuvant therapy were improved (0.25 vs 0.4, P = 0.013), but the absolute difference was small and unlikely to be of clinical significance (score of 0 representing no symptoms and 1 representing mild com- plaints).
They showed a mean Eastern Cooperative Oncology Group performance status during adjuvant therapy of 1.596 in the study group and 2.067 in the control (P = 0.002).
Tumor status was reported to be stable at 6 and 12 months; however, longer follow-up is necessary to evaluate the effect on survival and relapse, two critical outcomes of adjuvant therapy.

In palliative patients, improvement in quality of life is an important component of care and a key end point. 55
Yeom et al. investigated the effect of IV vitamin C(10 g twice a day for 3 days) on quality of life in 39 palliative patients. 56
They demonstrated a significant improvement in quality of life with higher scores for physical, emotional and cognitive function and lower scores for fatigue, nausea and vomiting, pain and appetite loss (both P < 0.005) in a single assessment 1 week posttreatment. 56
Although these results are suggestive of a benefit, with no control group a placebo effect cannot be excluded.
The duration of benefit was also not assessed. Cameron hypothesized palliative patients experience a strong “reverse placebo effect” because of previous treatment failures that counterbalance “placebo and anticipation” effects. 3,39
This has not been described in the literature elsewhere. Clinical pharmacokinetics Vitamin C has different functions at physiological and pharmacological plasma concentrations.
Oral vitamin C administration is associated with tightly controlled plasma concentrations regulated by the pharmacokinetic principles of bioavailability and clearance. 7
Saturation of bioavailability mechanisms occurs at oral doses of 400 mg daily equating to blood levels of 60–100 μM. 8
IV dosing bypasses this tight control, achieving plasma concentrations up to 20 mM. 7,8
In vitro evidence suggests plasma concentrations of 10 mM are necessary for an antitumor effect and this appears achievable clinically only with IV administration. 8
Padayatty et al. postulated that the vitamin C-free radical species, ascorbyl radical, forms only when human plasma concentrations are greater than 10 mM and that it is this radical or its unpaired electron that induces oxidative damage in cancer cells. 8
Casciari et al. published a trial to determine the dose necessary to achieve this level in humans. 57
In a single patient with colon cancer, they found that a dose of 60 g but not 30 g was effective at attaining this.

A recent phase I trial of 24 patients demonstrated that IV vitamin C to a dose level of 1.5 g/kg three times per week was safe and achieved plasma concentrations >10 mM for several hours. 58
While average follow-up was only 10 weeks, this trial did not demonstrate objective tumor response at these levels. 58

Riordan et al. published a series of 24 patients treated with IV vitamin C 150 mg/ kg/day and 710 mg/kg/day. 59
The mean plasma level was 1.1 mM (below the expected therapeutic target).
They did not demonstrate a correlation between dose and plasma concentration. The reason for this is unclear.
Other factors such as critical illness, renal function and chemotherapy regimens may alter plasma vitamin C concentrations and affect the plasma concentration necessary for cytotoxicity. 58

IS VITAMIN C SAFE ALONE AND IN CONJUNCTION WITH CHEMOTHERAPY AND RADIOTHERAPY?
Vitamin C is generally regarded as an innocuous compound with a favorable therapeutic index (Table 1).
While many centers have used high doses, there is limited published data around the safety at these doses.
Cases of acute hemolysis in patients with underlying glucose-6-phosphate dehydrogenase (G6PD) deficiency have been reported in patients treated with high-dose

Table 1
Side effects of intravenous vitamin C
Major side effects Glucose-6-phosphate deficiency
† Renal stones – particularly oxalate stones
† Tumor acceleration

Minor side effects
Dyspepsia, nausea and altered bowel habit
Increase iron absorption
‡ Raise urinary uric acid levels and excretion of calcium and iron 60

Fluid overload – caution in patients with ascites, heart failure
Interfere with routine laboratory parameters – B12, glucose and fecal occult blood

Side effects falsely attributed to vitamin C 60,61
Mutagenicity
Rebound scurvy
Infertility
Hypoglycemia
Destruction of vitamin B12

† Absolute contraindication to intravenous vitamin C.
‡ Important in patients with hemochromatosis.

vitamin C with at least one fatality described. 62,63
All patients should be screened for G6PD deficiency prior to starting vitamin C therapy. 62
Caution should also be taken in patients with a history of renal stones. 60
Acute obstructive renal failure secondary to oxalate stones has been reported in a patient with underlying renal impairment. 64
The effect of vitamin C on oxalate excretion is controversial with some believing excessive ingestion of AA increases the formation of oxalate stones. 60
In patients with widespread and rapidly proliferating tumors, vitamin C has been reported to cause tumor acceleration and precipitate tumor hemorrhage and necrosis. 37,65

The initial Cameron and Campbell trial described four patients in this category. 37
Potentially, this could also be explained by the natural history of the underlying cancer.
Dyspepsia, nausea and altered bowel habit are the most frequently reported side effects, particularly following oral administration. 59,60
High doses of oral vitamin C have been shown to affect iron absorption and interfere with many routine laboratory parameters. 59,60
In patients with congestive heart failure and ascites, the high fluid intake associated with administration may exacerbate their condition. 60


Role of vitamin C in combination with chemotherapy and radiation

The literature reports that 30–95% of patients with cancer try unconventional therapies, with the majority using these as adjuncts to their standard care with the intention to improve their quality of life and symptom control. 66–68
Despite this wide use, it remains unclear whether the concurrent use of antioxidants with chemotherapy and radiotherapy is beneficial or detrimental. 69 Because of the paucity of clinical trial evaluation, the evidence to date is mostly derived from in vitro and in vivo data, and observational records.
There are no published RCTs examining high-dose IV vitamin C in conjunction with chemotherapy or radiotherapy, making it difficult to definitively assess safety and efficacy.
Vitamin C has been studied in combination with a number of cytotoxic agents in vitro and in vivo with conflicting outcomes on efficacy 11,70–72 (see Appendix II).
It is theorized that vitamin C may sensitize refractory cancers to radiotherapy and chemotherapy. 11,70–73

Koch and Biaglow studied dehydroascorbic acid alongside radiation in hypoxic Ehrlich cells in ascites in vivo, demonstrating increased inhibition of cell growth with half the radiation dose. 74
Similar findings were found in neuroblastoma and glioma cell lines treated with 5-fluorouracil (5FU), sodium d-ascorbate and radiation. 75

Contrary to this, Witenberg et al. demonstrated a reduction in apoptosis from ionizing radiation in myeloid leukemia cells treated with dehydroascorbic acid. 76
This sensitizing effect is postulated to be due to the increased H 2 0 2 generation secondary to vitamin C administration.

However, vitamin C may also result in a reduction in HIF-1, which in xenograft models has been shown to be associated with heightened radiation sensitivity. 77
In keeping with this theory, putative small-molecule inhibitors of HIF-1 have demonstrated enhanced tumor responsiveness to radiation in vitro, supporting the use of this as a target in association with conventional therapies. 78

High-dose vitamin C is also postulated to reduce the toxicity of chemotherapy because of restoration of plasma vitamin C concentrations and thus antioxidant capacity. 54
In vitro evidence has also suggested that vitamin C may reduce the cardiac toxicity associated with doxorubicin without compromising efficacy, postulated to be related to peroxidation of cardiac lipids. 79

HOW CAN THE ISSUE OF THERAPEUTIC EFFICACY BE ADDRESSED IN THE FUTURE?
There are a number of trials underway in both the phase I and II setting (Table 2).
Although the methodology exists for investigating the role of high-dose vitamin C in cancer therapy, it is hindered by uncertainties including the target population and markers and predictors of response.
The inconsistency and current level of evidence to support a clear scientific rationale also makes the likelihood of funding for the necessary research problematic.
The ready availability and accessibility of IV vitamin C to patients makes a true placebo-controlled trial difficult, with crossover likely to be a major confounding factor.

Comparison of high-dose oral versus high-dose IV vitamin C (at least 1.5 g/kg three times per week as used in phase I trials) may address this, that is, low plasma concentration versus high (Table 3).
A third placebo-controlled arm could be added.
The target population remains unclear.
There is no clear cancer type or phase of care defined for the role of vitamin C.
In view of this, vitamin C could be trialed as an isolated treatment in patients who have exhausted conventional treatments.
An alternative approach would be to use vitamin C in patients on observation such as those with asymptomatic biochemical progression of ovarian or prostate cancer, asymptomatic pulmonary metastases 28

(...)
Current clinical trials

NCT00441207
A phase I study of high-dose IV vitamin C treatment in patients with solid tumors
Evaluate safety and tolerability of IV vitamin C.
Observe evidence of tumor response to vitamin C and compare the level of fatigue, pain control, quality of life before and after vitamin

NCT01050621
Phases I–II clinical trial of combination conventional cytotoxic chemotherapy and IV vitamin C in patients with advanced cancer or hematological malignancy for whom cytotoxic chemotherapy alone is only marginally effective
Dose escalation beginning with 0.9 g/kg escalating to 1.5 g/kg IV two to three times per week, bracketing chemotherapy
Evaluate safety and tolerability of IV vitamin C when administered alongside cytotoxic therapies.
To assess tumor response.
To assess effect on quality of life.
Determine the effect of chemotherapy on pharmacokinetics of IV vitamin C.

NCT01080352
Evaluation of cytotoxicity and genetic changes of high-dose IV vitamin C infusions in castration-resistant metastatic human prostate cancer
20 g IV vitamin C weekly PSA change after 12–20 weekly treatments.
Changes in bone metastases and markers of bone activity (bone-specific ALP, PINP, NTX).


NCT00626444
Pilot trial of IV vitamin C in refractory non-Hodgkin lymphoma (NHL)
IV vitamin C to achieve plasma level of 300–350 mg/dL given three times per week
Evaluate safety and tolerability of IV vitamin C and tumor shrinkage.


NCT00954525
IV vitamin C in combination with standard chemotherapy for pancreatic cancer
50, 75 or 100 g IV vitamin C three times per week
Evaluate safety and tolerability of IV vitamin C and tumor shrinkage.

(...)

Regardless of the population used, patient safety remains paramount.
All patients should have a G6PD screen and caution should be exercised in patients with a history of renal stones.
Baseline and on-treatment vitamin C levels should be assessed and used to titrate dose to achieve a concentration of at least 10 mM based on in vitro data. 8
This would help improve knowledge on the pharmacokinetic properties of vitamin C and help establish a dose–response relationship.
Based on experience gained from chemotherapeutic agents, further delineation of the mechanism of action may identify a target population with higher response rates.
If vitamin C acts via H 2 O 2 formation, population- based differences in the genotype and phenotype of catalase expression and activity may be relevant. 80 Those with low levels of catalase activity may be more sensitive to the effect and toxicity of high-dose vitamin C.
Assessment of this in a clinical trial would help determine if this theoretical sensitivity translates to clinical response.
It remains uncertain whether the use of vitamin C in conjunction with chemotherapy and radiotherapy has a beneficial or detrimental interaction.
Trials using vitamin C alongside chemotherapy need to include analyses of the pharmacokinetic properties of both vitamin C and the chemotherapeutic agent.
In vitro and in vivo data suggest vitamin C may overcome chemoresistance and improve chemosensitivity. 11,70–73
This has been demonstrated in vivo in pancreatic cancer cell lines in combination with gemcitabine, making this a potential population to start with. 11 Biopsies pre- and post treatment may help identify predictors and markers of response.
This has not been performed in the trials to date.
Method and timing of assessment of tumor response is hindered by our limited understanding of the mechanism of action and lack of specific biomarkers. Improvement of our translational knowledge is critical for future research.

Fluorodeoxyglucose-positron emission tomography could be used as a surrogate marker of response by assessing the effect of high-dose vitamin C on tumor metabolism.
There is evidence to support the use of PET to assess response to other modalities such as chemotherapy and chemoradiation. 81

CONCLUSION
Although the rates of utilization of vitamin C therapy remain uncertain, its popularity has increased over the years since the first suggestion of its chemo- therapeutic activity in the 1970s.

(...)

Table 3
Clinica trials
Population
1. Palliative patients with no further chemotherapeutic options
2. Alongside chemotherapy in refractory disease – ideal to use alongside one specific agent
3. One tumor subtype on observation alone, for example, good prognosis renal cell cancer
4. Across tumor subtypes based on initial data from Cameron trial Trial arms

Design of potential clinical trial
1. Comparison of oral high-dose (low plasma concentration) vitamin Cversus IV high-dose (high plasma concentration) vitamin C
2. Three arm trial with placebo versus oral high-dose vitamin C versus IV high-dose vitamin C
3. Placebo versus high-dose IV vitaminC
4. Similar arms as described above alongside chemotherapy or radiotherapy

Factors to be considered
1. Baseline and on-treatment assessment of plasma vitamin C levels
2. If alongside chemotherapy, pharmacokinetic studies of the chemotherapeutic agent Markers of response

Recommendations
1. Pre- and posttreatment biopsy if easily obtainable tissue
2. Catalase genotype evaluation as subgroup analysis to determine if there is a potential target population with increased efficacy
3. CT/MRI to assess response – timing of imaging remains controversial
4. PET-CT scan to assess tumor metabolic activity pre- and posttreatment

End points
1. Assessment of tumor response
2. Progression-free and overall survival
3. Quality of life assessment

† Addition of vitamin C alongside chemotherapy or radiation treatment has a number of ethical concerns because of the potential for both a beneficial or detrimental interaction.
Vitamin C could be studied in a population who have developed chemoresistance and have no further treatment options.

Currently no definitive evidence that IV vitamin C improves quality of life, progression-free or overall survival, the published RCT data do not negate potential benefit based on an improved understanding of vitamin C pharmacokinetics.
The pharmacokinetic properties of IVand oral vitamin C are critical in interpreting the data to date.
Based on in vitro data, it is now recognized that the plasma levels necessary for cytotoxicity requires IV dosing.
However, a phase I trial of 24 patients did not demonstrate objective responses despite using IV doses of up to 1.5 g/kg. 58
Vitamin C is well known for its antioxidant activity, but it is the proposed pro-oxidant activity at high concentrations that remains controversial.
This situation is perpetuated by the lack of a defined mechanism of action.
While intracellular and extracellular generation of H 2 O 2 is the most common theory, clarification of this and determination whether this will translate to a clinical benefit is critical in future research.
Although high-dose IV vitamin C appears relatively innocuous given alone, it does have the potential to cause harm in patients with G6PD deficiency and previous renal stones.
It remains uncertain whether vitamin C is clinically safe when given alongside chemotherapy and radiotherapy.
Despite 40 years of research since the initial reports on high-dose IV vitamin C, its use remains controversial.
The methodology exists to determine if high-dose IV vitamin C does have an anticancer effect, but the ability to design and conduct studies is impaired by the lack of a consistent scientific rationale, the ready availability and the use of this agent by practitioners already convinced by current evidence.
This makes a placebo- controlled trial difficult.
There are highly polarized views on the use of high- dose vitamin C for cancer treatment, with passionate advocates balanced by passionate critics.
This is a key reason for why carefully controlled clinical trials, rather than a review of the literature, are needed to obtain a clear view of this field.
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