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9. High-dose local irradiation plus prophylactic hepatic irradiation and chemotherapy for inoperable adenocarcinoma of the pancreas: a preliminary report of a multi-institutional trial (Radiation Therapy Oncology Group Protocol 8801)

Author

Komaki, R., Wadler, S., Peters, T., Byhardt, R.W., Order, S., Gallagher, M.J., Herskovic, A., and Pederson, J.

Subjects
Pancreatic cancer, Adenocarcinoma, Radiotherapy -- Usage, Liver cancer -- Prevention, Health
Abstract

Adenocarcinoma of the pancreas is an extremely malignant neoplasm with a particular propensity to spread to the liver> In an effort to combine chemotherapy with high-dose local irradiation plus a modest dose irradiation to suspected (subclinical) hepatic metastasis, patients with unresectable pancreatic carcinomas with no known distant metastasis were treated on a prospective multi-institutional Radiation Therapy Oncology Group (RTOG) Phase I/II trial. High total continuous radiation therapy to the pancreas (6120 cGy in 34 fractions over 7 weeks) and simultaneous prophylactic hepatic irradiation (PHI, 2340 cGy in 13 fractions for the last 2.5 weeks) were combined with administration of 5-flourouracil 1000 [mg/m.sup.2/day] (maximum, 1500 mg) by intravenous continuous infusion for 5 days starting on day 1 and repeated on day 30 for 5 days, followed by a dose of 600 [mg/m.sup.2] as a weekly bolus injection starting during week 9 for 6 months. In 18 months, 81 patients were enrolled in the study; 79 were evaluable with a minimum potential follow-up of 8.2 months. The patients ranged in age from 32 to 75 years (median, 64 years). Karnofsky performance status was 80 to 100 in 74% of patients. The tumor was confined to the head of the pancreas in 72% of patients. The planned radiation therapy for the pancreas was completed in 87% of patients, 80% received the planned PHI, and 85% completed the first two cycles of chemotherapy Seventy-five percent of patients completed both treatments according to the protocol. Most patients who did not complete both treatments had tumor progression or refused additional therapy. During all cycles of chemotherapy and radiation therapy, 2 patients died of complications (Grade 5, 1 hepatic and 1 infection), 9 had lifethreatening reactions (Grade 4, 7 hematologic, 1 neurologic, and 1 mucositis), and 31 patients had severe effects (Grade 3) according to the RTOG toxicity scale. Overall hepatic metastasis was documented in 32% as the first site of failure), persistent or progressive pancreatic tumor was evidence in 73%, and abdominal and extra-abdominal spread were reported in 27% and 8% of patients, respectively. Eighty percent (63 patients) died (median survival, 8.4 months). Although this study suggests that PHI may reduce the frequency of hepatic metastasis, failure to control the primary tumor and intraabdominal spread remain overwhelming. Cancer 1992; 69:2807-2812.

Published
1992

11. Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study

Author

Andreyev, HJN Norman, AR Cunningham, D Oates, J Dix, BR and Iacopetta, BJ Young, J Walsh, T Ward, R Hawkins, N and Beranek, M Jandik, P Benamouzig, R Jullian, E and Laurent-Puig, P Olschwang, S Muller, O Hoffmann, I and Rabes, HM Zietz, C Troungos, C Valavanis, C Yuen, ST and Ho, JWC Croke, CT O'Donoghue, DP Giaretti, W Rapallo, A and Russo, A Bazan, V Tanaka, M Omura, K Azuma, T and Ohkusa, T Fujimori, T Ono, Y Pauly, M Faber, C and Glaesener, R de Goeij, AFPM Arends, JW Andersen, SN and Lovig, T Breivik, J Gaudernack, G Clausen, OPF De Angelis, P Meling, GI Rognum, TO Smith, R Goh, HS and Font, A Rosell, R Sun, XF Zhang, H Benhattar, J and Losi, L Lee, JQ Wang, ST Clarke, PA Bell, S Quirke, P Bubb, VJ Piris, J Cruickshank, NR Morton, D Fox, JC Al-Mulla, F Lees, N Hall, CN Snary, D Wilkinson, K Dillon, D Costa, J Pricolo, VE Finkelstein, SD and Thebo, JS Senagore, AJ Halter, SA Wadler, S Malik, S and Krtolica, K Urosevic, N

Abstract

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes’ C cancers (failure-free survival. P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes’ B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. (C) 2001 Cancer Research Campaign.

Published
2001

12. Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: A frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial

Author

Augenlicht, L. H., Wadler, S., Corner, G., Richards, C., Louise Ryan, Multani, A. S., Pathak, S., Benson, A., Haller, D., and Heerdt, B. G.

Subjects
Carcinoma, Gene Amplification, Genes, myc, DNA, Neoplasm, Prognosis, Genes, p53, Survival Analysis, Gene Expression Regulation, Neoplastic, Chemotherapy, Adjuvant, Colonic Neoplasms, Mutation, Humans, Oncology & Carcinogenesis, Fluorouracil, Polymorphism, Single-Stranded Conformational
Abstract

Human colonic cancer is associated with multiple genetic deletions, mutations, and alterations in gene expression; in contrast, gene amplification has not been recognized as a prominent characteristic of human colonic tumors. Although the c-myc gene is overexpressed in approximately 70% of human colonic cancers, previous studies have not detected frequent gene amplification or rearrangement of c-myc in these tumors, although such amplification has been reported in chemically induced rodent colon cancer and quantitative analysis of gene copy number has shown the gene to be amplified at a low level in mucinous and poorly differentiated human colon carcinomas. Using rigorously controlled blot methodology, we have established that the c- myc gene, located at 8q21, exhibited amplification of 87% to 35-fold in 7 of 10 human colonic carcinoma cell lines. This was highly significant even at a low level of amplification in HT29 cells (P < 0.0001). Cytogenetic analysis by G-banding did not detect aneuploidy involving chromosome 8q, suggesting that the amplification for the c-myc gene on 8q was relatively specific, and this was consistent with a lack of amplification detected for the c-mos gene on 8q24, which was assayed similarly. The same methodology then revealed amplification of c-myc from 1.5-fold to 5-fold in 32% of tumors from 149 patients entered into a multi-institutional Phase III study of adjuvant therapy for colon cancer. c-myc status was not related to time to recurrence or death, but low levels of c-myc amplification identified a subset of patients who showed a statistically significant increase in disease-free survival, and a corresponding trend to longer overall survival, in response to adjuvant therapy with 5-fluorouracil plus levamisole. Presence of c-myc amplification was not related to incidence of p53 mutations.

Published
1997

13. Kirsten ras mutations in patients with colorectal cancer: the RASCAL II study

Author

Andreyev, HJN, Norman, AR, Cunningham, D, Oates, J, Dix, BR, Iacopetta, BJ, Young, J, Walsh, T, Ward, R, Hawkins, N, Beranek, M, Jandik, P, Benamouzig, R, Jullian, E, Laurent-Puig, P, Olschwang, S, Muller, O, Hoffmann, I, Rabes, HM, Zietz, C, Troungos, C, Valavanis, C, Yuen, ST, Ho, JWC, Croke, CT, O'Donoghue, DP, Giaretti, W, Rapallo, A, Russo, A, Bazan, V, Tanaka, M, Omura, K, Azuma, T, Ohkusa, T, Fujimori, T, Ono, Y, Pauly, M, Faber, C, Glaesener, R, de Goeij, AFPM, Arends, JW, Andersen, SN, Lovig, T, Breivik, J, Gaudernack, G, Clausen, OPF, De Angelis, P, Meling, GI, Rognum, TO, Smith, R, Goh, HS, Font, A, Rosell, R, Sun, XF, Zhang, H, Benhattar, J, Losi, L, Lee, JQ, Wang, ST, Clarke, PA, Bell, S, Quirke, P, Bubb, VJ, Piris, J, Cruickshank, NR, Morton, D, Fox, JC, Al-Mulla, F, Lees, N, Hall, CN, Snary, D, Wilkinson, K, Dillon, D, Costa, J, Pricolo, VE, Finkelstein, SD, Thebo, JS, Senagore, AJ, Halter, SA, Wadler, S, Malik, S, Krtolica-Žikić, Koviljka, Urosevic, N, Andreyev, HJN, Norman, AR, Cunningham, D, Oates, J, Dix, BR, Iacopetta, BJ, Young, J, Walsh, T, Ward, R, Hawkins, N, Beranek, M, Jandik, P, Benamouzig, R, Jullian, E, Laurent-Puig, P, Olschwang, S, Muller, O, Hoffmann, I, Rabes, HM, Zietz, C, Troungos, C, Valavanis, C, Yuen, ST, Ho, JWC, Croke, CT, O'Donoghue, DP, Giaretti, W, Rapallo, A, Russo, A, Bazan, V, Tanaka, M, Omura, K, Azuma, T, Ohkusa, T, Fujimori, T, Ono, Y, Pauly, M, Faber, C, Glaesener, R, de Goeij, AFPM, Arends, JW, Andersen, SN, Lovig, T, Breivik, J, Gaudernack, G, Clausen, OPF, De Angelis, P, Meling, GI, Rognum, TO, Smith, R, Goh, HS, Font, A, Rosell, R, Sun, XF, Zhang, H, Benhattar, J, Losi, L, Lee, JQ, Wang, ST, Clarke, PA, Bell, S, Quirke, P, Bubb, VJ, Piris, J, Cruickshank, NR, Morton, D, Fox, JC, Al-Mulla, F, Lees, N, Hall, CN, Snary, D, Wilkinson, K, Dillon, D, Costa, J, Pricolo, VE, Finkelstein, SD, Thebo, JS, Senagore, AJ, Halter, SA, Wadler, S, Malik, S, Krtolica-Žikić, Koviljka, and Urosevic, N

Abstract

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes C cancers (failure-free survival. P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. (C) 2001 Cancer Research Campaign.

Published
2001

35. Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: A frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial

Author

Augenlicht, LH, Wadler, S, Corner, G, Richards, C, Ryan, L, Multani, AS, Pathak, S, Benson, A, Haller, D, Heerdt, BG, Augenlicht, LH, Wadler, S, Corner, G, Richards, C, Ryan, L, Multani, AS, Pathak, S, Benson, A, Haller, D, and Heerdt, BG

Abstract

Human colonic cancer is associated with multiple genetic deletions, mutations, and alterations in gene expression; in contrast, gene amplification has not been recognized as a prominent characteristic of human colonic tumors. Although the c-myc gene is overexpressed in approximately 70% of human colonic cancers, previous studies have not detected frequent gene amplification or rearrangement of c-myc in these tumors, although such amplification has been reported in chemically induced rodent colon cancer and quantitative analysis of gene copy number has shown the gene to be amplified at a low level in mucinous and poorly differentiated human colon carcinomas. Using rigorously controlled blot methodology, we have established that the c- myc gene, located at 8q21, exhibited amplification of 87% to 35-fold in 7 of 10 human colonic carcinoma cell lines. This was highly significant even at a low level of amplification in HT29 cells (P < 0.0001). Cytogenetic analysis by G-banding did not detect aneuploidy involving chromosome 8q, suggesting that the amplification for the c-myc gene on 8q was relatively specific, and this was consistent with a lack of amplification detected for the c-mos gene on 8q24, which was assayed similarly. The same methodology then revealed amplification of c-myc from 1.5-fold to 5-fold in 32% of tumors from 149 patients entered into a multi-institutional Phase III study of adjuvant therapy for colon cancer. c-myc status was not related to time to recurrence or death, but low levels of c-myc amplification identified a subset of patients who showed a statistically significant increase in disease-free survival, and a corresponding trend to longer overall survival, in response to adjuvant therapy with 5-fluorouracil plus levamisole. Presence of c-myc amplification was not related to incidence of p53 mutations.

Published
1997

36. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study

Author

Andreyev, H J N, primary, Norman, A R, additional, Cunningham, D, additional, Oates, J, additional, Dix, B R, additional, Iacopetta, B J, additional, Young, J, additional, Walsh, T, additional, Ward, R, additional, Hawkins, N, additional, Beranek, M, additional, Jandik, P, additional, Benamouzig, R, additional, Jullian, E, additional, Laurent-Puig, P, additional, Olschwang, S, additional, Muller, O, additional, Hoffmann, I, additional, Rabes, H M, additional, Zietz, C, additional, Troungos, C, additional, Valavanis, C, additional, Yuen, S T, additional, Ho, J W C, additional, Croke, C T, additional, O’Donoghue, D P, additional, Giaretti, W, additional, Rapallo, A, additional, Russo, A, additional, Bazan, V, additional, Tanaka, M, additional, Omura, K, additional, Azuma, T, additional, Ohkusa, T, additional, Fujimori, T, additional, Ono, Y, additional, Pauly, M, additional, Faber, C, additional, Glaesener, R, additional, Goeij, A F P M de, additional, Arends, J W, additional, Andersen, S N, additional, Lövig, T, additional, Breivik, J, additional, Gaudernack, G, additional, Clausen, O P F, additional, Angelis, P De, additional, Meling, G I, additional, Rognum, T O, additional, Smith, R, additional, Goh, H-S, additional, Font, A, additional, Rosell, R, additional, Sun, X F, additional, Zhang, H, additional, Benhattar, J, additional, Losi, L, additional, Lee, J Q, additional, Wang, S T, additional, Clarke, P A, additional, Bell, S, additional, Quirke, P, additional, Bubb, V J, additional, Piris, J, additional, Cruickshank, N R, additional, Morton, D, additional, Fox, J C, additional, Al-Mulla, F, additional, Lees, N, additional, Hall, C N, additional, Snary, D, additional, Wilkinson, K, additional, Dillon, D, additional, Costa, J, additional, Pricolo, V E, additional, Finkelstein, S D, additional, Thebo, J S, additional, Senagore, A J, additional, Halter, S A, additional, Wadler, S, additional, Malik, S, additional, Krtolica, K, additional, and Urosevic, N, additional

Published
2001
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39. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

Author

Swain, S M, primary, Whaley, F S, additional, Gerber, M C, additional, Weisberg, S, additional, York, M, additional, Spicer, D, additional, Jones, S E, additional, Wadler, S, additional, Desai, A, additional, Vogel, C, additional, Speyer, J, additional, Mittelman, A, additional, Reddy, S, additional, Pendergrass, K, additional, Velez-Garcia, E, additional, Ewer, M S, additional, Bianchine, J R, additional, and Gams, R A, additional

Published
1997
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