From: Subject: Intravenously administered vitamin C as cancer therapy: three cases -- Padayatty et al. 174 (7): 937 -- Canadian Medical Association Journal Date: Mon, 15 May 2006 09:29:41 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_002D_01C67802.17D23E40" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_002D_01C67802.17D23E40 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.cmaj.ca/cgi/content/full/174/7/937 Intravenously administered vitamin C as cancer = therapy: three cases -- Padayatty et al. 174 (7): 937 -- Canadian = Medical Association Journal

 

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CMAJ =95 March 28, 2006; 174 (7). = doi:10.1503/cmaj.050346.
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Research

Intravenously administered vitamin C as cancer therapy: three cases=20

Sebastian = J.=20 Padayatty, Hugh D. Riordan, Stephen M. = Hewitt,=20 Arie Katz, L. John Hoffer and Mark = Levine=20

From the Molecular and = Clinical=20 Nutrition Section, Digestive Diseases Branch, National Institute of = Diabetes and=20 Digestive and Kidney Diseases (Padayatty, Katz, Levine), and the = Laboratory of=20 Pathology, Centers for Cancer Research, National Cancer Institute = (Hewitt),=20 National Institutes of Health, Bethesda, Md.; Lady Davis Institute for = Medical=20 Research (Hoffer), McGill University, Montr=E9al, Que.; = Bio-Communications=20 Research Institute (Riordan) (deceased), Wichita, Kan.

Correspondence = to:=20 Dr. Mark Levine, Molecular and Clinical Nutrition Section, Bldg. 10, = Rm=20 4D52=96MSC 1372, National Institutes of Health, Bethesda MD = 20892=961372; MarkL{at}mail.nih.gov


3D""    Abstract=20
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E= arly=20 clinical studies showed that high-dose vitamin C, given by=20 intravenous and oral routes, may improve symptoms and prolong = life in=20 patients with terminal cancer. Double-blind placebo-controlled=20 studies of oral vitamin C therapy showed no benefit. Recent=20 evidence shows that oral administration of the maximum = tolerated=20 dose of vitamin C (18 g/d) produces peak plasma = concentrations=20 of only 220 =B5mol/L, whereas intravenous administration = of the=20 same dose produces plasma concentrations about 25-fold = higher. Larger=20 doses (50=96100 g) given intravenously may result in plasma=20 concentrations of about 14 000 =B5mol/L. At concentrations = above 1000=20 =B5mol/L, vitamin C is toxic to some cancer cells but not to = normal=20 cells in vitro. We found 3 well-documented cases of advanced = cancers,=20 confirmed by histopathologic review, where patients had = unexpectedly=20 long survival times after receiving high-dose intravenous = vitamin C=20 therapy. We examined clinical details of each case in = accordance with=20 National Cancer Institute (NCI) Best Case Series guidelines. = Tumour=20 pathology was verified by pathologists at the NCI who were = unaware=20 of diagnosis or treatment. In light of recent clinical=20 pharmacokinetic findings and in vitro evidence of anti-tumour = mechanisms, these case reports indicate that the role of = high-dose=20 intravenous vitamin C therapy in cancer treatment should be=20 reassessed.

Thirty years ago Cameron, Campbell and Pauling reported beneficial=20 effects of high-dose vitamin C (ascorbic acid) therapy for = patients=20 with terminal cancer.1<= SUP>=964 = Subsequent double-blind, randomized clinical trials at the = Mayo=20 Clinic failed to show any benefit,5<= SUP>,6<= SUP>=20 and the role of vitamin C in cancer treatment was discarded = by=20 mainstream oncologists.7<= SUP>,8 = Vitamin C=20 continues, however, to be used as an alternative cancer=20 therapy.9<= SUP>,10=20

A key distinction between conventional, science-based medicine = and=20 alternative therapy is the presence or absence of scientific=20 plausibility.11In=20 conventional medicine, the efficacy of treatment is proven by = properly conducted clinical trials. Many treatments are still = used if=20 there is moderately good, albeit inconclusive evidence of = efficacy=20 ("clinical plausibility"), especially when treatment = rationale agrees=20 with biologic facts (conferring "biological = plausibility").11 Vitamin=20 C is an alternative cancer therapy because the results = obtained in=20 original studies that suggested clinical benefit were not = confirmed=20 by controlled clinical trials, and the notion that high-dose = vitamin=20 C was selectively toxic to cancer cells was biologically=20 implausible.

New information is available pertaining to biological = plausibility.=20 Although similar doses of vitamin C were used in the = Cameron=96Pauling=20 and Mayo Clinic studies, the Cameron=96Pauling studies = combined=20 intravenous and oral administration whereas the Mayo Clinic=20 studies used only oral administration.1<= SUP>,2<= SUP>,12=9614=20 Recent pharmacokinetics modeling15indicates=20 that with oral administration, even very large and frequent = doses of=20 vitamin C will increase plasma concentrations only modestly, = from 70=20 =B5mol/L to a maximum of 220 =B5mol/L, whereas intravenous=20 administration raises plasma concentrations as high as 14 000 = =B5mol/L. Concentrations of 1000=965000 =B5mol/L are = selectively=20 cytotoxic to tumour cells in vitro,16=9620and=20 emerging evidence indicates that ascorbic acid at = concentrations=20 achieved only by the intravenous route may function as a = pro-drug for=20 hydrogen peroxide delivery to tissues.20 The in=20 vitro biologic evidence and clinical pharmacokinetics data = confer=20 biological plausibility to the notion that vitamin C could = affect=20 cancer biology and may explain in part the negative results = of the=20 Mayo Clinic trials.13,15,21,22 Thus,=20 sufficient evidence has accumulated, not to use vitamin C as = cancer=20 treatment, but to further explore the therapeutic concept. = One way to=20 increase the clinical plausibility of alternative cancer = therapies is=20 rigorous, well-documented case reporting, as laid out in the = US=20 National Cancer Institute (NCI) Best Case Series guidelines = (http://www3.cancer.go= v/occam/bestcase.html).23,24=20 Such case series might identify alternative therapies that = merit=20 further investigation.23,24=20

Case reports of apparent responses by malignant disease to = intravenous=20 vitamin C therapy have appeared,25=9630=20 including those of 2 of the 3 patients presented = below.25,26=20 However, they were reported without sufficient detail or with = incomplete follow-up for evaluation and without conforming to = NCI=20 Best Case Series guidelines. They also lacked objective = pathologic=20 confirmation, which is a pillar of NCI guidelines. In this = article,=20 we use NCI Best Case Series guidelines to report 3 cases of=20 patients with usually progressive malignant disease who = received=20 intravenous vitamin C therapy as their only significant = cancer=20 therapy and whose clinical courses were unusually favourable. = Original diagnostic material obtained before treatment with = vitamin C=20 was reviewed by pathologists at the National Institutes of = Health=20 (NIH) who were unaware of the diagnoses and treatments. =


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<= SUP>



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  		Fig. 1: Chest = radiography, November=20 1996, about 1 month after intravenous vitamin C therapy was = started.=20 Cannonball lesions are evident in both lung fields, as = indicated by=20 the arrows and lines. =

 = ;
This=20 case was previously reported but without long-term follow-up, = without=20 detail, and with no independent pathologic confirmation.25,26=20 A 51-year-old woman was found in August 1995 to have a tumour = involving her left kidney. At nephrectomy in September 1995=20 this was shown to be a renal cell carcinoma 9 cm in diameter=20 with thrombus extending into the renal vein. Chest = radiography=20 results were normal, and there was no evidence of metastatic=20 disease on CT scan of the chest and abdomen. In March 1996 a = CT=20 scan of the chest indicated several new, small, rounded and=20 well-defined soft tissue masses no larger than 5 mm in = diameter;=20 they were judged consistent with metastatic cancer. By = November=20 1996 chest radiography revealed multiple cannonball lesions = (Fig. = 1).=20


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  		Table 1. =

 = ;
The=20 patient declined conventional cancer treatment and instead = chose to=20 receive high-dose vitamin C administered intravenously at a = dosage of=20 65 g twice per week starting in October 1996 and continuing = for 10=20 months. She also used other alternative therapies: thymus = protein=20 extract, N-acetylcysteine, niacinamide and whole thyroid = extract (Table = 1). In June=20 1997 chest radiography results were normal except for one = remaining=20 abnormality in the left lung field, possibly a pulmonary scar = (Fig. = 2).=20



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  		Fig. 2: Chest = radiography, June=20 1997, showing regression of the lesions; the arrow indicates = one=20 residual abnormality. =

 = ;

In October 2001 a new mass 3.5 cm in diameter in the anterior=20 right lung was detected on radiography. A transthoracic = biopsy=20 revealed small-cell carcinoma of the lung. The patient opted=20 for intravenous vitamin C injections. The lung mass remained=20 constant in size in radiograpy taken in May and August 2002 = but=20 had increased to 4 cm in views taken in October 2002. In = early=20 November hyponatremia developed. Two weeks later the patient = was=20 admitted to hospital with abdominal distension and constipation.=20 Barium studies revealed slow transit but no intestinal = obstruction.=20 Results of a CT scan of the abdomen were normal. She died = shortly=20 afterward, and no autopsy was performed. Histopathologic = review=20 of the primary renal tumour at the NIH confirmed the = diagnosis=20 of clear-cell renal carcinoma, type, nuclear grade III/IV, = with=20 the largest diameter measuring 6.5 cm. The tumour involved = the=20 renal vein and hilar perinephric fat. Pathologic review of = the=20 lung tumour biopsy specimen of October 2001 was not conducted = at the NIH. Local pathologists diagnosed this specimen as = indicating=20 small-cell lung cancer and not recurrent metastatic renal = cell=20 carcinoma.

This case describes the regression of pulmonary metastatic renal = cancer in a patient receiving high-dose intravenous vitamin = C=20 therapy. According to the NCI Best Case Series guidelines, = the=20 credibility of this case would be increased by biopsy proof = that the=20 multiple slowly growing bilateral cannonball lung nodules in = this=20 patient with known renal cell carcinoma were actually = malignant.=20 However, in this case, the clinical characteristics and = evolution of=20 the pulmonary lesions, in the absence of bacterial infection = or other=20 systemic disease, make any other diagnosis unlikely. The = clinician=20 attending the patient deemed a confirmatory biopsy to be = unnecessary=20 and inappropriate in this setting. A plausible alternative=20 explanation to the conclusion that this patient's metastatic = renal=20 cell cancer responded to intravenous vitamin C therapy is = that the=20 tumours spontaneously regressed. Spontaneous regression has = been=20 reported in renal cell cancer, but it is rare, occurring in = fewer=20 than 1% of cases and typically after nephrectomy, radiation = to the=20 primary tumour or primary tumour embolization.31,32 Here,=20 metastatic disease appeared several months after = nephrectomy,=20 rather than regressing in response to it. As well, the = primary cancer=20 was nuclear grade III/IV and involved the renal vein, factors = associated with a highly unfavourable prognosis.31=20

Of note, more than 4 years after stopping intravenous vitamin = C=20 therapy and with the renal cell cancer in complete remission, = primary=20 small-cell lung cancer was diagnosed in this patient, who was = a=20 long-standing cigarette smoker. The second cancer did not = respond to=20 high-dose vitamin C therapy. From the clinical history it = appears the=20 tumour remained a constant size for many months and likely = slowly=20 progressed until her death about a year after diagnosis = despite the=20 resumption of intravenous vitamin C therapy.


3D""    Patient 2=20
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A= =20 49-year-old man presented to his physician in 1996 with hematuria = and=20 was found at cystoscopy to have a primary bladder tumour with = multiple satellite tumours extending 2=963 cm around it. = Transurethral=20 resection of the primary tumour and its surrounding tumour = satellites=20 was carried out until apparently normal muscle was reached = and the=20 tumour base was fulgurated. The patient declined systemic or=20 intravesical chemotherapy or radiotherapy and instead chose=20 intravenous vitamin C treatment. He received 30 g of vitamin = C twice=20 per week for 3 months, followed by 30 g once every 1=962 = months for 4=20 years, interspersed with periods of 1=962 months during which = he had=20 more frequent infusions. Histopathologic review at the NIH = revealed a=20 grade 3/3 papillary transitional cell carcinoma invading the=20 muscularis propria. Now, 9 years after diagnosis, the patient = is in=20 good health with no symptoms of recurrence or metastasis. The = patient used the following supplements: botanical extract,=20 chondroitin sulfate, chromium picolinate, flax oil, = glucosamine=20 sulfate, 3D{alpha}-lipoic acid, Lactobacillus acidophilus and L. = rhamnosus=20 and selenium (Table = 2).=20


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  		Table 2. =

 = ;

Complete or partial bladder removal is the standard treatment = for=20 stage T2 (muscle invasive) bladder cancer, since the presence = of=20 muscle invasion appears to be the best predictor of aggressive=20 behaviour. When treated only locally, as in this case, = invasive=20 transitional cell bladder cancer almost invariably develops=20 into clinically apparent local or metastatic disease within = a=20 short period.33=9635 There=20 are reports of transurethral tumour resection being offered = as the=20 sole initial therapy in carefully selected patients with T2 = disease.=20 In one report 20% of patients with muscle invasive bladder = cancer=20 treated only with transurethral resection remained free of = recurrent=20 disease after 3=967 years of follow-up.36However,=20 such minimal therapy is considered an option only when the = cancer is=20 solitary, well defined and completely excised as documented = by=20 pathologic evaluation,37=20 whereas this patient presented with multiple tumours and = associated=20 muscle invasion.


3D""    Patient 3=20
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T= his case=20 was previously reported but without detail and without = independent=20 pathologic confirmation.26,30 A=20 66-year-old woman was found in January 1995 to have a large = left=20 paraspinal mass medial to the iliopsoas muscle at the L4=965 = level. On=20 imaging the mass measured 3.5=967 cm transversely and 11 cm = in the=20 craniocaudal direction, with evidence of extension into the=20 posterior paraspinal muscle and bone invasion. Chest = radiography=20 results were normal. An open biopsy specimen was diagnostic = of=20 a diffuse large B-cell lymphoma. The patient's oncologist = recommended=20 local radiation therapy and chemotherapy. Although she agreed = to a=20 5-week course of local radiation therapy, the patient refused = chemotherapy, electing instead to receive vitamin C = intravenously.=20 She received 15 g of vitamin C twice per week for about 2 = months, 15=20 g once to twice per week for about 7 months, and then 15 g = once every=20 2=963 months for about 1 year. This began in mid-January 1995 = concurrently with the radiation therapy, which was given as = AP/PA=20 parallel opposed 18 MEV x-rays and between 1=9618 and = 2=9628=9695,=20 5040 Centi Gray in 28 fractions delivered to the mid-plane of = the body with 3:2 loading from the back. At this time a left=20 axillary lymph node 1 cm in diameter and a right axillary = lymph=20 node 1.5 cm in diameter were palpable.

Two weeks later, in early February 1995, the right and left=20 axillary lymph nodes remained palpable and a new left = cervical=20 lymph node 1 cm in diameter and a new left supraclavicular = lymph=20 node larger than 1 cm were apparent on physical examination.=20 Intravenous vitamin C therapy continued. Three weeks later = the=20 supraclavicular and cervical lymph nodes were no longer = palpable,=20 the left axillary node had disappeared, and the right = axillary=20 node had decreased in size to less than 1 cm. After a further = 3=20 weeks, in mid-March 1995, there was no lymphadenopathy in the = neck=20 and no palpable axillary lymphadenopathy. In late April 1995 = a new=20 left cervical lymph node was detected, and histopathologic = review=20 identified a biopsy specimen as identical to the original = tumour. The=20 patient once again refused chemotherapy and continued her = program of=20 intravenous vitamin C injections. Two months later, in June = 1995,=20 there was marked left supraclavicular lymphadenopthy 3 cm in = size,=20 with shotty right axillary nodes but no adenopathy in the = left=20 axilla. Four months later, in October 1995, a single right=20 submandibular node was palpable, but the supraclavicular and = all=20 other areas, including the axillas, had no palpable lymph = nodes. In=20 May 1996 a left anterior cervical node 1.5 cm in size was = present,=20 but there was no other adenopathy. Intravenous vitamin C = therapy=20 continued through late December 1996, at which time the = patient was=20 in normal health and had no clinical sign of lymphoma. The = patient=20 remains in normal health 10 years after the diagnosis of = diffuse=20 large B-cell lymphoma, never having received chemotherapy. = The=20 patient used additional products: =DF-carotene, = bioflavonoids,=20 chondroitin sulfate, coenzyme Q10, = dehydroepiandrosterone,=20 a multiple vitamin supplement, N-acetylcysteine, a botanical=20 supplement and bismuth tablets (Table = 3).=20 Histopathologic examination of the original paraspinal mass = at the=20 NIH confirmed a diffuse large B-cell lymphoma at stage III, = with a=20 brisk mitotic rate.


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  		Table 3. =

 = ;

Patients with untreated stage III diffuse B-cell lymphoma have = a=20 dismal prognosis. This case, like the preceding one, is unusual = in=20 that the patient refused chemotherapy, which might have produced = a=20 long-term remission. It appears, nonetheless, that a cure = occurred in=20 connection with intravenous vitamin C infusions.


3D""    Discussion=20
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T= hese=20 cases were analyzed in accordance with the NCI's Best Case = Series=20 process, which reports and interprets apparent responses to=20 alternative therapies.23,24 Apart=20 from its implications regarding vitamin C, this article = illustrates=20 the use of the Best Case Series approach in assessing the = clinical=20 plausibility of novel therapies. None of these case histories = provides definitive proof that intravenous vitamin C therapy = was=20 responsible for the patient's unusually favourable clinical = course.=20 It is often difficult to prove definitively that a given = treatment is=20 responsible for a specific clinical outcome. When the = treatment is=20 unorthodox, alternative explanations, even if highly = unlikely, tend=20 to be preferred.38,39=20 However, although they do not provide grounds for advocating=20 intravenous vitamin C therapy as a cancer treatment, these = cases=20 increase the clinical plausibility of the notion that = vitamin=20 C administered intravenously might have effects on cancer = under=20 certain circumstances.

The overall plausibility of ascorbic acid administered = intravenously=20 as a cancer therapy is enhanced by recent insights into = clinical=20 pharmacokinetics and in vitro cancer-specific cytotoxicity of = vitamin C.15=9620=20 Pharmacokinetics data show that orally administered vitamin C = results=20 in tightly controlled plasma and cell concentrations. = Subjects=20 consuming 200=96300 mg per day of vitamin C in 5 or more = daily servings=20 of fruits and vegetables have fasting steady state plasma=20 concentrations of about 70=9680 =B5mol/L.40,41 Even=20 with maximally tolerated oral doses of 3 g every 4 hours, = peak plasma=20 concentrations are estimated to not exceed 220 = =B5mol/L.15Intravenous=20 administration of vitamin C bypasses tight control for = several hours,=20 until homeostasis is restored by renal excretion. Depending = on=20 the dose and infusion rate, peak plasma concentrations = obtained=20 intravenously are estimated to reach 14 000 =B5mol/L, and=20 concentrations above 2000 =B5mol/L may persist for several = hours.=20 Emerging in vitro data show that extracellular ascorbic acid=20 selectively kills some cancer but no normal cells by generating=20 hydrogen peroxide.20 Death=20 is mediated exclusively by extracellular ascorbate, at = pharmacologic=20 concentrations that can be achieved only by intravenous=20 administration. Vitamin C may serve as a pro-drug for = hydrogen=20 peroxide delivery to extravascular tissues, but without the = presence=20 of hydrogen peroxide in blood. These data are consistent with = clinical pharmacokinetics of vitamin C administered=20 intravenously.15Of note,=20 only a minority of cancer patients reported by Cameron and = colleagues=20 responded to intravenous and oral vitamin C therapy,1<= SUP>=964a= nd not=20 all cancer cells were killed by ascorbic acid in = vitro.20 Further=20 basic investigation of pharmacologic vitamin C concentrations = in=20 mediating cell death will facilitate discovery of the = mechanisms=20 responsible for sensitivity and resistance in vitro and in = vivo. On=20 the basis of emerging clinical and in vitro data, early-phase = clinical trials of intravenous vitamin C therapy alone and in = combination with conventional chemotherapy are currently in = the=20 planning and execution phase, including a formal phase I = trial in=20 progress at McGill University.42=9644=20

The cases reported here do not prove that vitamin C induced = the=20 favourable outcomes observed. These patients received other=20 alternative medicine therapies. Spontaneous remission of some = tumours may occur rarely, although the 3 cancers reported = here=20 are dissimilar. Accretion of more cases meeting NCI Best Case = Series guidelines may indicate whether vitamin C or other = factors=20 contribute to such remissions.

It is likely that high vitamin C intakes have low toxicity, = except=20 under certain conditions.45,46=20 Intravascular hemolysis was reported after massive vitamin C=20 administration in people with glucose-6-phosphate = dehydrogenase=20 deficiency.46Administration=20 of high-dose vitamin C to patients with systemic iron = overload=20 may increase iron absorption and represents a = contraindication.46,47Ascorbic=20 acid is metabolized to oxalate, and 2 cases of acute oxalate=20 nephropathy were reported in patients with pre-existing renal = insufficiency given massive intravenous doses of vitamin C.48,49Therefore,=20 patients with renal insufficiency or renal failure, or who = are=20 undergoing dialysis, should not receive high doses of vitamin = C.46 It is=20 controversial whether high-dose vitamin C use is associated = with=20 oxalate kidney stones, and patients with hyperoxaluria or a = prior=20 history of oxalate kidney stones have a relative = contraindication to=20 high-dose vitamin C.46Rare=20 cases of acute tumour hemorrhage and necrosis were reported = in=20 patients with advanced cancer within a few days of starting = high-dose=20 intravenous vitamin C therapy, although this was not = independently=20 verified by pathologic review.1<= SUP>,50=20 Although tumour hemorrhage suggests an anticancer potential = for=20 ascorbate, there is the potential for risk to some = patients.=20

The cases reported here are of tumours confirmed by = histopathologic=20 examination to have poor prognosis but that instead had long=20 clinical remissions. Most previous case reports lacked = independent=20 pathologic confirmation of the tumour and did not follow the=20 NCI Best Case Series guidelines, which makes their = interpretation=20 difficult. Recent findings show that only high-dose = intravenous,=20 but not oral, vitamin C therapy results in very high plasma=20 vitamin C concentrations (e.g., 14 000 =B5mol/L). At these=20 concentrations, the vitamin is toxic to some cancer cells, = possibly=20 because at these concentrations the vitamin is a pro-drug for = hydrogen peroxide formation in extracellular fluid. = Accumulated=20 data confer some degree of biological and clinical = plausibility=20 to the notion that high-dose intravenous vitamin C therapy = may=20 have anti-tumour effects in certain cancers. When all = available=20 data are considered, further clinical study as to safety and=20 efficacy of intravenous vitamin C is warranted.

@ See related article page 956=20


3D""    Footnotes=20
 
Editor's take =

=95 Intravenous administration of the maximum tolerated dose = of=20 vitamin C produces plasma levels 25 times that achieved when = the same=20 dose is administered orally. At high plasma concentrations = vitamin C=20 is toxic to some cancer cells but not to normal cells in = vitro.=20

=95 Using the National Cancer Institute Best Case Series = guidelines,=20 the authors reviewed 3 cases of advanced cancer where = patients had=20 unexpectedly long survival times after receiving high-dose=20 intravenous vitamin C therapy.

Implications for practice: In a setting of biological=20 plausibility and clinical plausibility, further research into = vitamin=20 C as a treatment for cancer is warranted.

This article has been peer reviewed.

Contributors: Sebastian Padayatty, Arie Katz and Mark = Levine=20 wrote the first draft, Hugh Riordan contributed to data = acquisition,=20 Stephen Hewitt conducted pathology reviews and John Hoffer = revised=20 this article. All of the authors contributed to the = conception,=20 design and critical review of the paper. All of the authors=20 approved the final version of the paper, excepting Hugh = Riordan.=20 Hugh Riordan died before the final version was accepted but = had=20 reviewed and approved an earlier version of the paper.

Acknowledgements: The writing of this paper was supported = in=20 part by the Intramural Research Program of the National = Institute=20 of Diabetes and Digestive and Kidney Diseases, National = Institutes=20 of Health (Z01 DK 54506).

Hugh D. Riordan died suddenly during the final preparation of = this=20 article. We dedicate it to his memory.

Competing interests: None declared.



3D""    REFERENCES=20
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&nb= sp;

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  5. Creagan ET, Moertel CG, O'Fallon JR, et al. Failure of = high-dose=20 vitamin C (ascorbic acid) therapy to benefit patients with advanced = cancer. A=20 controlled trial. N Engl J Med 1979;301:687-90.[Abstract]
  6. Moertel CG, Fleming TR, Creagan ET, et al. High-dose = vitamin C=20 versus placebo in the treatment of patients with advanced cancer who = have had=20 no prior chemotherapy. A randomized double-blind comparison. N Engl = J=20 Med 1985;312:137-41.[Abstract]
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S.=20 Assouline and W. H. Miller
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Content-Location: http://www.cmaj.ca/js/rollover.js function MM_swapImgRestore() { //v3.0=0A= var i,x,a=3Ddocument.MM_sr; = for(i=3D0;a&&i0&&parent.frames.length) {=0A= d=3Dparent.frames[n.substring(p+1)].document; n=3Dn.substring(0,p);}=0A= if(!(x=3Dd[n])&&d.all) x=3Dd.all[n]; for = (i=3D0;!x&&i.=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_002D_01C67802.17D23E40 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.cmaj.ca/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= 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quoted-printable Content-Location: http://www.cmaj.ca/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. 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