[Pathology] Supplemental Ascorbate in the Supportive Treatment of Cancer: 1. Prolongation of Survival Times in Terminal Human Cancer * (vitamin C, ascorbic acid) EWAN CAMERON and LINUS PAULING Vale of Leven District General Hospital, Loch Lomondside. G83 OUA, Scotland and Linus Pauling Institute of Science and Medicine, 2700 Sand Hill Road, Menlo Park, California 94025, U.S.A. Contributed by Linus Pauling 1976 *Publication no. from the Linus Pauling Institute of Science and Medicine 2. ABSTRACT Ascorbic acid metabolism is associated with a number of mechanisms known to be involved in host resistance to malignant disease. Cancer patients are significantly depleted of ascorbic acid, and in our opinion this demonstrable biochemical change (in cancer) indicates a substantially increased requirement and utilization of this substance to energize these various host resistance factors. The results of a clinical trial are presented in which 100 terminal cancer patients were given supplemental ascorbate as part of their routine manage ment. Their progress is compared to that of 1000 similar patients treated identically, but who received no supplemental ascorbate. The mean survival time is 4.06 times as great for the ascorbate subjects (204 days) as for the controls (50 days). The results clearly indicate that this simple and safe form of medication is of definite value in the treatment of patients with advanced cancer. 4. The study involved a treated group of 100 patients with terminal cancer of various kinds and a control group of 1000 untreated and matched patients. (No ,patients with lung .cancer were included; they are treated in another hospital. ) The treated group consists of 100 patients who began ascorbate treatment, as described by Cameron and Campbell4 (usually 10 g per day, by intravenous infusion for about 10 days and orally thereafter), at the time in the progress of their disease when in the considered opinion of at least two independent clinicians the continuance of any conventional form of treatment would offer no further benefit. (There is one exception, Case 80, who is Case 45 of Ref. 4 and the subject of Ref. 5. As is explained in these papers, he was started on the ascorbate treatment while waiting for high-energy radiation therapy, and has received no treatment other than ascorbate. ) Fifty of the treated subjects are those described in Ref. 4 (with, however, different case numbers) and the other fifty were obtained by random selection from the alphabetical index of ascorbate-treated patients in Vale of Leven District General Hospital, where treatment of some terminal cancer patients with ascorbate had been begun in November 1971. We believe that the ascorbate- treated patients represent a random selection of all of the terminal patients in this hospital, even though no formal randomization process was used. ,Four of the treated patients (Cases 17, 59, 80, and 84) were in Hairmyres Hospital; they are included because they had been included in the group described in Ref. 4, and it seemed unwise to us to omit them. In the 5. random selection three patients were excluded because supplemental ascorbate treatment had been discontinued by order of another physician and five were excluded because matching controls could not be found for them. Patients known to have voluntarily discontinued ascorbate treatment have been retained in the group, as have those who died from some cause other than their cancer. No patient was excluded because of short survival time. h The survival times of the 19 patients * marked with a Z&G correspond to the date 10 July 1976, on which they were still alive. Ten control cases for each treated case were selected by random search of the index for the last ten years in Vale of Leven Hospital. All ten control cases match the treated case as to kind of cancer, sex, and age of the patient (to within five years). The case of pseudomyxoma (91) was difficult to match, requiring search of the records for 20 years; this case was included, despite this difficulty, because of its inclusion in Ref. 4. Selection of the 1000 control cases was made by Frances Meuli, M.B., Ch. B. (Otago), who was given the sex and age of the patient and the type of cancer for each of the 100 treated cases, but who had no knowledge of their survival times. She determined from the records the date at which each control patient was classified as untreatable,' from the establishment of moper-ability at laparotomy, the abandonment of any definite form of cancer treatment, or the final date of admission for "terminal care. " We thank Dr. Meuli for her valuable contribution to 6. this investigation. Even though no formal process of randomization was carried out in the Felection of our two groups, we believe that they come close to representing random subpopulations of the population of terminal cancer patients in Vale of Leven Hospital, There is some internal evidence in the data in Table 1 to support this conclusion. The results of the study are given in Table 1` and summarized in Table. 2, in which values for different kinds of cancer represented by 7 or more patients treated with ascorbate (70 or more controls) are shown. For each of the eight categories the ratio of average days of survival (ascorbate/controls) is greater than unity, the range for the eight categories being from 2. 5 to 7.4, with 4.06 for all 100 patients. The ratios are somewhat uncertain; for example, omitting the patient with longest survival in the colon group would decrease the ratio from 7.4 to 5.2. At the present time we cannot conclude that ascorbate has less value for one kind of cancer than for others. Our conclusion is that the administration of ascorbic acid in amount about 10 g per day to patients with advanced cancer leads to about a four-fold increase in their life expectancy, in addition to an apparent improvement in the quality of life. This great increase in survival time results from the much larger numbers of the ascorbate patients than of the controls who live for long times, as is shown in Figure 1. Sixteen percent of the patients treated with ascorbic 7. acid survived for more than a year, fifty times the value for the controls (0.3%). Statistical analysis shows that the null hypothesis that the treatment with ascorbate has no benefit is to be rejected for each of the categories in Table 2. The results of a simple statistical test are given in the table. A reasonable dividing line, the average survival time for all subjects, is given in column E, and the percentages exceeding this value are given in columns F and G. Column I-E contains the values of xa obtained by a two-by-two calculation, and I gives the corresponding values of P (one- tailed). Similar values are obtained by non-parametric methods. The fraction of survivors at time t after the initial date (determination of nontreatability) is given to within &O. 01 by the expression exp(-at ), in which t is the survival time in days and cy has the value 0.021 d -1 . This expression corresponds to a constant mortality rate for this group of untreated patients with terminal cancer, and its validity suggests that for them a single random process, occurring with a probability independent of time, leads to death. For the group of patients treated with ascorbate the same expression with Q about 0.007 d -1 approximates the fraction of survivors up to about 100 days, after which a larger fraction of survivors is found, reaching about 0.07 beyond 600 days. A simple interpretation of these facts is that the administration of ascorbate to the patients with terminal cancer has two effects. First, it increases the effectiveness of the natural mechanisms of resistance to such an extent as to lead to an increase by 3 in the average survival time for all patients; 3 is the ratio of the two values of cy. 0.021 and 0.007. Second, it has another effect on about 7 percent of the patients, such as to cause them to live a much longer time. This effect might be such as to "cure" them; that is, to give them the life expectancy that they would have had if they had not developed cancer. On the other hand, it might only set them back one or more stages in the development of the cancer, in which case their life expectancy would be somewhat less than that corresponding to complete elimination of the effect of their having developed cancer. This uncertainty may be eliminated in the course of time, as the survival times of the 19 patients in the ascorbate-treated group who were still living in 10 July 1976 become known. Conclusion In this study the times of survival of 100 ascorbate-treated cancer patients in Scotland (measured from the day when the patient was pronounced to have cancer untreatable by conventional methods) have been discussed in comparison with those of 1000 matched controls, 10 for each of the ascorbate-treated patients. The data indicate that deaths occur for about 93 percent of the ascorbate-treated patients at one third the rate for the controls, so that for this fraction there is a threefold increase in survival time, measured from the date when the cancer was pronounced untreatable. For the other 7 percent of the ascorbate-treated patients the survival time is not known with certainty, but it is indicated by the values in Table 1 to be more than 22 times the average for the untreated patients. The value 4.06 (Table 2) for the ratio 9. of average survival times expresses the resultant of these two effects (note that 93 percent of 3 plus 7 percent of 22 equals 4.33). We conclude that there is strong evidence that treatment of Scottish patients with terminal (untreatable) cancer with about 10 g of ascorbate (ascorbic acid, vitamin C) per day increases the survival time by the factor 3 for most of them and by at least 22 for a few (about 7 percent). It is our opinion that a similar effect would be found for untreatable cancer patients in other countries. Larger amounts than 10 g per day might have a greater effect. Moreover, we surmise that the addition of ascorbate to the treatment of patients with cancer at an earlier stage of development might well have a similar effect, changing life expectancy after the stage when ascorbate treatment is begun from, for example, five years to twenty years. We have begun studies along this line. This study was supported by research grants fromThe Secretary of State for Scotland and The Educational Foundation of America. 10. References 1. Cameron, E. & Pauling, L. (1973) "Ascorbic acid and the glycosamino- glycans: An orthomolecular approach to cancer and other diseases", Oncology _27, 181-192. 2. Cameron E. & Pauling, L. (1974) "The orthomolecular treatment of cancer. I. The role of ascorbic acid in host resistance", Chem. -Biol. Interactions 9, 273-283. 3. Cameron, E. (in press) "Biological function of ascorbic acid and the pathogenesis of scurvy: a working hypothesis", Medical Hypotheses. 4. Cameron, E. & Campbell, A. (1974) "The orthomolecular treatment of cancer, II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer",Chem. -Biol.Interactions 9, 285-315. 5. Cameron, E., Campbell, A., & Jack, T. (1975) "The orthomolecular treatment of cancer, III. Reticulum cell sarcoma: double complete regression induced by high-dose ascorbic acid therapy", Chem. -Biol. Interactions 11, 387-393. - Table 1 Comparison of time of survival of 100 cancer patients who received ascorbic acid and 1000 matched patients with no treatment a Primary Case Tumor SuAival time. (days) No. Type Sex Age Ten matched controls - - .---- _ -u_z 1. STOMACH 2. STOMAa 3. .STOYACH 4. STOMACH. 5. STOMACH. 6. STOMACH 7. STOMACH 8. STOMACH 9. STOMAai 10. sToNAcH . F 61 12 M 69 8 F .62` 1s F 66 4 M 42 a M 79 4s M 76 22 id 54 24 M 62 14 F 69 -6 43. -6 1 87 1 4 19 26 23 19 s -. 29 . 3 9 72 19 7 .I1 74 358 12 1 12 9 21 61 13 89 5s 2 I 85 '124 4- 26. 19 3 9 9 14 27 4 21 .- 27 I3 a4 6 7 48 . 11 . a I `a 54 -21 36 a 114 15 14 35 99' 7ij 111 -12 6' 34. 35' 14 16. 16 128 12 130 4 r1 15 3 5 -14 7 26 2 221 4 4 36 27 53 11 103 17 . . .. * . 38.5 20.7 47.4 . 21.2 70.8 23.4 12.0 46.i 22.5 29.5 Tesi Test cas Mean case mea- -. 121 314% Ai!. 58% . 9 - 19 t 18 85% - 258 368: 43 Ia.? s - . 142 1183.9 ?6_ * 7t.t rig+' $$?a.o - 1c)2+ g a -. . . . . . .l. SlDMACIi t-1 45 .2. STCMACH M Si -3. BRONCHUi M 74 . .4. BRONCHUS M 74 . .S. BRONCHUS M 66 .6: BRONUiUS M' 52 -7. BRONCHUS F. 48 .8. BRONCHUS F 64 .9. 'BRONCHUS M 70 !O. BRONCHUS M 7a !l. BRONCHUS. M .71 !2. BRONCHUS M 70 !3. BRONCHUS 'M 39' !4;-BRONCHwS--~--M--70.-- !S. BRONCHUS M 70 ?6. OESOPHAGUS M 72 !7. OESOPHdGUS F 80 . - !8. COLON F 76 !9. COLON, F 58 30. COLON M 49 . 31. .COLON M 69 32. COLON - F 70 13. COLoN 'P 68 34. U3LON * M SO 3s. COILJN F 74 . 17 '24 19 13 -. l-6 21 47 3s 11 7 24 '32 S 3 42 24. a 12 2` 2 56 56 z . 94 4 33 1 a 19 s3 2 31 .l 34 21 29 2 39 -- 35' '122 , . I . . .< . - . . *. . : . I -7 57 128 16 44 . 64 ltd. 78 - a ILL 39 29 .*. 4 1 17 170 ,s . -2g. -- 27 67 41' 25 26. 6 i0 -27: 30 18 '1 31 1'. 21 -16 . 7'39 3 53 S 4 J-9 70 30 26 20 39 7 33 74 30 29 19 21 126 . a 46 '272 39. 7s S -.6'. 1 45 24 .-8l 57 13 1 :71 14 4 30 103 2 7 40 30 24 S 2 26 14 62 20 - S 41 19 49 . 24 21 43 103 2 21 : 2. s 20 39 31 16 . 2s is 2s 62. a2 6; 88... .45,.- 28. ._.. 3 _.. 15.' -. k 5' : 42. 46 41 . i7 S7' . -. s;`4 . 32 129'.`. 20 5% 81' i6*`-. 59 2i 28 3? . . : . 48 i4 _ y- 238 . 56 ? .20- .- 2; . y-- 1 4 - ',I1 9." 11 8 10 ,i 62 I 1 6 -45 18 s 31 1s' 107 28 * 48 9 7. is 64 102 13 82 9 1s 40 11 7 108 7' 18 11 4s so '6 30 13 ia 65 46 56. 30 90 26 94' 38 15 a 51 33 144 '17 o '11 . 17 -217 163 S9 la .3'c; 17 14- 51 is 16 (32). 18 26 40 11 88 23 M 66 ' 36. COLON 13 7 224 31 37. COIRN 'P 76 i ; 23 129 . -a 63 - 38. COLON F 56 i . 1 24 30 2 - _ S 42 46 41 7 S7 72 11 1 4 11 -14 - . 66 -21 28 3 ts 70 39. RECTUM P 56 i 51 406 74 36. 41 106 30. 82 82 98 PECTUM . 40. = ps- i ; 3 40 46 58 7 9 . 19 -68 16 178 ; - . . . - . -- __ --'- ---y-z 2-z ;Ir-A-LS ,- . . 54.5 L?.z 150% 36.9 6q' 173't 33.3 3q 117 t 16.8 427 2542% 34.3 17 5.9 ' o 69.6 460 661 * __. 29.3 - E` '307 %- . 27.1 i8i 690 % 25.5 58 ;,227 s- __ . . 34.4 ,52_ .lSf. t 20.8 100. .4a1 % 27.4 m Qlr\ - 40.1 42.. lOf;r . 25.5 167 -655% .40.7 o z :' 81% . 57.4 : ; -'So_ .87%. 4k.3 43. . 9a* 7.6 " 57 75d't 2.4.7 32 .l& .- 58.0 _ pm,. .34p. 37.3 -I '1267 .4343% -. - . 52.5 144'. 274%. 38.5 170 :44+ 33.-a 428 %266% 3i,a . E+ 394% 38.8 ss_ 149: 43.8 cj3+ 22= . 25.5 86l- 3376% i0.6 .: 62 62-s - 44.4. 223- 502% * . - 41. RECPUM .- 42. RECTUM 43. RECTUM 44. RECTUM 45. RECTUM. 46.' OVARY - 47. ovmr m 40. OVARY . 49. OVARY - SO. OVARY 51. BREAST 52. BREAST S3. BREAST 54. BNCAST' 55. BREAST 56. BREAST - 57. BREAST 58. BREAST 59. BREriT 60. BREAST 61.. BREAST 62. BLADDER 63. BLADDER 64. BLADDER. 65. BLADDER 66. BLADDER 67. BLADDER . . 68. BLADDER f . .M'S6 F` 57. M -6; M 54. M 59: F 49 . F. 6-i F 49. F 67 J+ 56 F 56 C- F . . 57 F -ii F 66 F 68 'F 53 F 75 F 74 . F 49 F SO' F 53 M 93` F 70' F 73 P -77 M 44 M 62. - 'i! 69 69. GALLBLADDER F 71 70. `GAI~LBLP.DDER k' 67 - . . . . . - . `J: - ' 3 .-18 -52 36 34 7 49 .3 6 (13) 9' 73'11 19 98 82 (184) (97) (89) . ($) . 11:. 11 91 47 .18 23 4 13 79 84' SC 36 - 10 I.27 18. 98 6 : .7..3 l-> 19 . _ ', 1s' '2 36. 5 41 39 53.. 15 19.; 36 49 39 1'. 65 3 28 33 183 22 12 07 42 8 2 45 17s 12. 2 3 . 16 31 29. OS 73' 17 47 39. 9 1 23 3 -52 - " 78 8 98 30 140. 54 233 (14)` -1i7 29 31 18. 37 k7 22 101 140 94. 73 U? -38.' 122 .68 3 91 40 ;6 12 22 . 2 '10 . . .._ 22 -8s i60 26. -. 6 ..f. 2 1s '.4- ':I4 6 ;90- :'.SS 33 a41 ._ 18. . 21 '40 . . 32 48 132 21 ii 1 86` 106 . . 99 1(-y iS 19 io2 71 131 .: I i6 14 48 61 -- 15 . . 26 16 45 109 -. . .: 94. 5s :- . 7- 38 2: 10 76 li . 69 . 19 .-II?. is1 101 'al 50 s?, .. 2 42 . 31 17 96 231 42 2d __. '. * ."I 12 -91` 27 S 20 11. 63 33 -: 1; - . 35 6 33 30 107 ..F I j; 47 I 62 -44 '.l I7 93 73 s . . 28 40 ;6S ;ss '14 '3i 24. .104 +' lr 193 159 .; 0 127 126 167 74 . 21 12 .. 2 18 21 46 -1;; ?? 48 126 -52 26 97 10 8 7 52.' : ;. 78 30 38 38 2s 13 45: 2:4. - ' 48 142, 118 34 33 10 38 ;i . . - :- 6.9 -36 48 10 21 8 52 42 . I-- . f.6---' 47 '118 85 76 19 58 127 - 72 i<- 2; 39: - S 66".26- 25 ;67 85 12" .1; . 27 . 7 a 56. 22 91 44 30 22 47 14. 1 -: 20 ls'9 - - 4 212 73 60 -94 - 31 16 9l' -- -. . . - . -. . - . 0. - -. -5 . s . -. . -..:. I .a .. . . .: --- . * 818 22.2. x- . 10.9 223 314,s 38.1 "iti+ ++ . ., qS.0 198 440~0 -: 67.2 759 1129% 64.8 226 -. 349% 3s.s. 33' . . - ., p! o 124.9 183':. 1;16% . .- . . L . 43:0. 4 3 b , -. -!: . 21.8' -22 - - kg.0 s7k' I-?J.% -- s35 % f02.8 E'/ 3&b 78.8 567 &% . 49.1 86 ITS % 74.2 590 79s a- . .37.s- g i 2i s- 37.i .35' _- . . ?4 * 82-6 &4+_195~% 107.1 1y3+ 134% 36.5 241 660% 4s,3 253 556,Om 28.9 110 3ap so.4 . 34 57% 24.8 ;34 '.~ 13?% 62.7 &'fo/& 56.5. -;o. 5:' j4.i - 22 .-. .X4% . 76;O. '209 275%; . . -- 71. XIDNEY(Ca) F 71 72. KIDNEY(Ca)' `F 63 73. KIKPJgY(Ca) .F 51 74. KIDNEY(Ca)' M 53 75. xIDNEY(Ca). M SS 76. KImBY M 73 77. x1 DE;LY (Ca) M 45 78. XIDSEY(Pap) ti 69 79 XI DNEY (Pap) M 74 93 FYMPHOMA M 40 81 LYMPHOMA M 65 4 a2 PROSTATE M 47 83. UTERUS F. 56 84. ff!ONDhOSARCOMA Ns.63 85. 'BRAIN' M 49' 86. PANCREAS.' M 77 87. PANCREAS M -67 88. PANCREAS Fa 89. FIBRCSARaMA F 54 90. TESTICLE M 42 91. PSEUDOMYXOMA M 47 92. CARCINOID F 68 93. LEIOMYOSARCOMA F32 94. LEUXAEMIA F 59' 9s. S?DMAQi M .ss 96. OVARY F 51 97. BRONCHUS ? 69 o ? 98. BRONCHUS .E 67 99. COLCJN .- M '77' 00. COLON M 38 6 68 16 7 1s 25 91 67 57 144 I 28 24 '25 20 1 11 112 11. 13..: l/171.. __ 10' 30 64 (101) (9) (?S) (?7! 11 ld- j' 5.6 46 -39 102 17 (19) 35 16'..i- '. (q .(8,7) 19.. (37) (27) (-12) (1s) (97) (i6?:?' 19 12' 45 - - 8 31 12 18 1s 8? i38) . 31 74 ;' 66. (26) (87)(121) .t213 l44p @lf2?2j 6 36 183 .6 36 32 44 36 112 .$i - . . 34 34 12 '78 .S 2S3 -77 79 72 45' ,'J(l 76 31 13. 65 216 62 140 92 *30- 90 '160 62 $0 43 137 32 20 . - - 1?5 l'$' 93 -20. '29 90 97 68 lb5 8 37 25 - 8 .- 69 80 14 30 9 57 68 . 14 &- 3 41' 78 17 ! -58 $6. 66 98 y -ii i8b) : . : . . - . . f ".' . . - I' . . 2. i7 .b3 81 . . - 'Si 14 114 60 10'6 . 76 - '8 31 26. .S 8 69 29 ;] 49 82. 27 41 65 29 8 125 (9Sj h;7] 15 .7 49 9s 'il. 9% . 3s 19 76 13 12 16 45 - d8- -89 . 95 6 .8,3. 11' 209 19 30 198 31 7 30 so , - . 35 19 77 66. .12 127 74 !4 82. . 74 (24) (37)',87* 43* 21* 82* 14* ?I+ 67.-- Sl (49'1)(;27)' 324 174 126*-I-79* 97* 41:. 53 16 29. 20 41 274 $2 - li? 68' Sl 56 117 138 10 36 il 142. 14 22 -23 lo1 53 157 123 .:' 16 80 _ . _- 11 -. . 7 ** -67. 130 126 30 18: i& 25':. 3. . ;7+ 136 -.17. 31 23 19: -157. fjl 85.' , ..-. 56' (187) 57 24 13 =29 . ;A qs 25 19 38' 91 :7a 13 41: 40 94. ._ . 6 sS` .-36 ;S6 ;5 91 7Q' 67 ii * . - 42;. 23 49 57 69 122 - 253.' $9. .!y; . . . 53.8 176 ' 32'7% -- . .36.9 8q 24&s 60.6 147 -, .2434 41.5 'x l~/b%: . ;:: 42.2 659 1562% 61.0 293 - 4"1 61.5 1. '-+m - 49.0 24 49%. - -. . . 169.3 d24_+ +o$- 102.8 9!%+ 961% . 69.7 82 jlj' 82.3 13& l$rm 66.0 id - -. iO3.P 44.8' 9- .-2d -. 54.8 g '6?;- .: . 4 41.6 s ;,36.% 42.1 132 "j21% 28.0 ,132+ 1;;7!% 74.1` +92i+ '5710 - . 55.4' wso++ qz!20, 69.3 2& 394' 37,s 82 . .I$', 87.4 31 ;3S%. 65.9 Ijs ; ;;+ 37.0 Is -40% 52.3 &+ 4334 - - (Footnote to Table 1) a The sign + following the survivaltime of the patients treated with ascorbic acid means that the patient was alive on 10 July 1976. Parantheses ( ) indicate that the matched patient had the same sex, same kind of tumor, and same dissemination, but had an age difference greater than 5 years. Brackets [ ] indicate opposite sex, same tumor, same dissemination, age difference greater than 5 years. +Diffuse urinary tract papillomatosis. The test cases (78 and 79) had lesions in both kidney and bladder. The nine control cases indicated by the asterisk had tumor of identical histology, but with their disease confined to bladder mucosa. Table 2 Ratios of Average Survival Times for Ascorbate Patients and Matched Controls, with Statistical Significance A Bronchus (15) Colon (13) Stomach ( 13) Breast (11) Kidney (9) Bladder (7) Rectum (7) Others (2 5) All (100) B C D E 134d 38.5d 3.48 47d 275 37.0 7.42 59 94.3 37.9 2.49 43 362 64.0 5.66. 91 330 64.0 5. 16 88 192 222 158 4.00 71 2.62 72 204.2 43. 6 55. 5 60.2 50.3 4.39 57 4.06 64 F G 47% 8. 7% 54% 20% 46% 17% 55% 22% 67% 22% 57% 20% 86% 33% 44% 28% 61% 25% H 24. 5 7. 63 6.41 5.74 8.35 4.90 7.57 2.64 57.66 I