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management of metastatic ca colon with chemotherapy evolution in ca colon.pptx

  1. Management Of Metastatic Carcinoma Colon and Evolution of Chemotherapy Dr Kartik Kadia MMIMSR, Ambala
  2. Metastatic Ca Colon • Approximately 50% to 60% of patients diagnosed with CRC develop metastases* • 20–30% of newly diagnosed patients present with unresectable metastatic disease* • Metastatic disease most frequently develops metachronously after treatment for locoregional CRC, with the liver being the most common site of involvement* * Perez and Brady’s Principals of Radiation Oncology – 7th Edition
  3. Metastatic Sites in Ca colon • The Liver is the most common site of metastasis from CRC; this is thought to be due to the venous drainage of the colon and rectum. • Approximately 50% of CRC patients develop liver metastasis during the course of the disease* *Treatment of hepatic metastases from colorectal cancer: many doubts, some certainties.Biasco G, Derenzini E, Grazi G, Ercolani G, Ravaioli M, Pantaleo MA, Brandi G Cancer Treat Rev. 2006 May; 32(3):214-28.
  4. • The Lungs are the second most common site of distant metastases from CRC • Studies have shown that 10%-15% of patients with CRC develop lung metastases during the course of the disease Metastatic Sites in Ca colon *Characteristics of recurrence and surveillance tools after curative resection for colorectal cancer: a multicenter study.Kobayashi H, Mochizuki H, Sugihara K, Morita T, Kotake K, Teramoto T, Kameoka S, Saito Y, Takahashi K, Hase K, Oya M, Maeda K, Hirai T, Kameyama M, Shirouzu K, Muto T Surgery. 2007 Jan; 141(1):67-75. Lung nodule in Patient of CA Colon*
  5. • In retrospective studies of CRC patients, the rate of peritoneal metastases has been reported to be between 4% and 13%, making it 3rd most common site of Metastasis Metastatic Sites in Ca colon * Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies.Koppe MJ, Boerman OC, Oyen WJ, Bleichrodt RP Ann Surg. 2006 Feb; 243(2):212-22.
  6. • The incidence of Brain metastases in patients with CRC has been reported to be between 0.3% and 6% in different series – 4th most common site of Metastasis Metastatic Sites in Ca colon * Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System.Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE J Clin Oncol. 2004 Jul 15; 22(14):2865-72.
  7. • The incidence of Bone metastasis from CRC has been reported, with signet-ring cell pathology showing a high incidence of bony metastases • There are only a few case reports of CRC with isolated metastases to the adrenal gland** and the spleen*** Metastatic Sites in Ca colon – Other Organs Involved *Bone metastasis from colorectal cancer in autopsy cases.Katoh M, Unakami M, Hara M, Fukuchi S J Gastroenterol. 1995 Oct; 30(5):615-8. **Adrenalectomy for solitary adrenal metastasis from colorectal cancer: A case report.Kosmidis C, Efthimiadis C, Anthimidis G, Levva S, Ioannidou G, Zaramboukas T, Emmanouilides C, Baka S, Kosmidou M, Basdanis G, Fachantidis E **Isolated splenic metastasis from colorectal cancer.Abi Saad GS, Hussein M, El-Saghir NS, Termos S, Sharara AI, Shamseddine A Int J Clin Oncol. 2011 Aug; 16(4):306-13.
  8. TNM – 8th Edition Staging
  9. TNM – 8th Edition Staging
  10. Metastatic Ca Colon • M1a:  Metastasis to only one site/solid organ (e.g., liver, lung, ovaries, nonregional lymph node)  external iliac, common iliac, para-aortic, supraclavicular, or other nonregional LNs  Multiple metastases within only one organ, even if the organ is paired (e.g., the ovaries or lungs), is still M1a disease. • M1b: Metastases to multiple sites or solid organs • M1c: Peritoneal carcinomatosis with or without blood-borne metastasis to visceral organs occurs in 1-4 % of patients and prognosis for peritoneal disease is worse than that for visceral metastases to one or more solid organs
  11. Management • Surgery • Local therapies • Chemotherapy
  12. • Only few patients with liver and/or lung-isolated metastatic disease, are potentially curable with surgery • Other patients with mCRC, treatment is palliative and generally consists of systemic chemotherapy
  13. Synchronous Liver Only Or Lung Only Metastases Treatment modality is decided on basis of : • Resectable or • Unresectable
  14. For resectable lesions • Colectomy with synchronous resection of liver or lung metastases followed by adjuvant chemotherapy with FOLFOX or CapeOx • Neoadjuvant CT to increase curative resection rates * Perez and Brady’s Principals of Radiation Oncology – 7th Edition
  15. For unresectable lesions • Treatment is with chemotherapy and evaluation every 2 months to assess resectability of liver and/or lung metastases, colon resection if risk of obstruction or significant bleeding * Perez and Brady’s Principals of Radiation Oncology – 7th Edition
  16. For patients that are able to undergo resection of metastatic disease: • 6 months of adjuvant therapy with an active regimen for advanced disease, observation, or shortened course of palliative chemotherapy is preferred * Perez and Brady’s Principals of Radiation Oncology – 7th Edition
  17. Surgery • For select group of patients with metastatic CRC, complete surgical resection of stage IV disease may be an option which may or may not provide a long-term survival advantage. • Some patients with initially unresectable metastatic disease may also become candidates for curative procedures based on their response to chemotherapy
  18. Recommendation for Surgery • Patients with resectable metastatic disease and a primary tumor in place should have both sites resected with curative intent. • These can be resected in one operation or as a staged approach, depending on the complexity of the hepatectomy or colectomy, comorbid diseases, surgical exposure, and surgeon expertise.
  19. Hepatic Resection • Hepatic resection is the treatment of choice for resectable liver metastases from colorectal cancer. • Complete resection must be feasible based on - anatomic grounds and the extent of disease; maintenance of adequate hepatic function
  20. Local Therapies for Metastases For Non surgical Candidates with Resectable metastatic disease: • Radiofrequency ablation (RFA) • Organ-specific infusional therapy: Hepatic Arterial Infusion (HAI) with fluorouracil and folinic acid. • Cryotherapy, • Trans-Arterial Chemo-Embolisation (TACE) with drug-eluting beads; • Radioembolization with Yttrium-90 • SBRT
  21. RFA • Radiofrequency ablation (RFA) is an approach to destroying inoperable primary or metastatic tumors in the Liver. • With ultrasound guidance, a probe is inserted through the liver tissue into the tumor. • This probe delivers high frequency alternating electrical current precisely at the site of the tumor. • The current generates heat that burns out the tumor
  22. Hepatic arterial infusion (HAI) • Hepatic Arterial Infusion (HAI) is a procedure that delivers chemotherapy directly to the liver. • The procedure, mostly used in combination with systemic chemotherapy, which plays a role in the treatment of liver metastases • Principal of HAI : The liver derives its blood supply from two sources – the hepatic arterial circulation and the portal circulation.
  23. • Cathater inserted allows for chemotherapeutic drugs to be delivered directly to the cancer cells if infused into the hepatic artery. • Most common drug infused is Floxuridine Hepatic arterial infusion (HAI)
  24. Transarterial Chemoembolization (TACE) • Transarterial chemoembolization or TACE places – chemotherapy drugs and synthetic materials called embolic agents into a blood vessel feeding a cancerous tumor to – cut off the tumor's blood supply and trap the chemotherapy within the tumor
  25. Radioembolization • Radioembolization is a minimally invasive procedure that combines embolization and radiation therapy to treat liver cancer/metastasis • Tiny glass or resin beads filled with the radioactive isotope yttrium Y-90 are placed inside the blood vessels that feed a tumor
  26. Unresectable metastatic CRC • Management depends around – palliation and control of symptoms, control of tumor growth, and attempts to lengthen progression-free survival and OS • Chemotherapy • Palliative Surgery
  27. • Issue of whether patients presenting with unresectable stage IV disease should have their primary tumors resected or not has been the matter of controversy
  28. • A review of seven nonrandomized studies*, totaling 1086 patients, concluded that resection of the primary cancer in asymptomatic patients with unresectable stage IV disease was not associated with a consistent improvement in overall survival and did not significantly reduce the risk of primary site complications (obstruction, perforation, bleeding) *Cirocchi R, Trastulli S, Abraha I, Vettoretto N, Boselli C, Montedori A, Parisi A, Noya G, Platell C. Non- resection versus resection for an asymptomatic primary tumour in patients with unresectable stage IV colorectal cancer. Cochrane Database Syst Rev. 2012 Aug 15;(8):CD008997. doi: 10.1002/14651858.CD008997.pub2. PMID: 22895981.
  29. Palliative Surgery • Indicated in cases of – impending obstruction, perforation, bleeding, or pain.
  30. Resection of cancer and primary anastomosis -Diverting end colostomy with mucous fistula -Bypass procedure • Associated with high postoperative morbidity and mortality. Palliative Surgery
  31. Nonsurgical palliative options • Intraluminal stent placement Local palliation of an obstructing or nearly obstructing tumor.
  32. Why Chemotherapy in Ca Colon with metastasis • Patients with mCRC undergoing surgery/receiving supportive care have been shown to have a poor prognosis, with a median overall survival (OS) of 5 months. * Perez and Brady’s Principals of Radiation Oncology – 7th Edition
  33. • By contrast, patients with mCRC who receive chemotherapy have been shown to have a median OS of more than 2 years • The drugs traditionally used in colorectal cancer still are the mainstay. * Perez and Brady’s Principals of Radiation Oncology – 7th Edition Why Chemotherapy in Ca Colon with metastasis
  34. • Major advances in systemic chemotherapy have expanded the therapeutic options for these patients and improved median survival from – less than 1 year to 30 months or longer for selected patients, and up to 20 percent of those treated with chemotherapy alone still remain alive at five years * Perez and Brady’s Principals of Radiation Oncology – 7th Edition Why Chemotherapy in Ca Colon with metastasis
  35. Evolution Of Chemotherapy in Colorectal Carcinomas
  36. • The German chemist Paul Ehrlich was the first person to coin the term ‘chemotherapy’ during his work on the use of chemical agents to treat infectious diseases in the early 1900s* • However, the evolution of chemotherapy for CRC can be said to have begun with the development of 5-fluorouracil (5-FU) in 1957* Paul Ehrlich
  37. • Charles Heidelberger and colleagues at the University of Wisconsin observed that tumor tissues preferentially used uracil for nucleic acid biosynthesis, and correctly postulated that a fluorouracil analogue would inhibit tumor cell division by blocking the conversion of – deoxyuridine monophosphate (dUMP)  deoxythymidine monophosphate (thymidylate)
  38. • Biochemical studies demonstrated that the main route of 5-FU activation proceeds via complex metabolic pathways that result in the formation of 5- fluorodeoxyuridine monophosphate (FdUMP), a potent inhibitor of thymidylate synthase
  39. • The level of inhibition of thymidylate synthase achieved with 5- fluorodeoxyuridine monophosphate (FdUMP) in patients was shown to correlate with the clinical response to 5-FU treatment* • Studies of the molecular mechanism of thymidylate formation identified the transient formation of a ternary complex consisting of – substrate dUMP, the folate cofactor 5,10-methylenetetrahydrofolate (MTHF), and thymidylate synthase.
  40. • The next key advance in the development of 5-FU-based chemotherapy was the finding that inhibition of thymidylate synthase by 5-FU could be potentiated by increased intracellular levels of reduced folates*
  41. Side effects of Fluorouracil • Diarrhea • Nausea and possible occasional vomiting • Mouth sores • Poor appetite • Watery eyes, sensitivity to light (photophobia) • Taste changes, metallic taste in mouth during infusion • Discoloration along vein through which the medication is given • Low blood counts
  42. Leucovorin • In a pivotal in vitro study of the biomodulation of 5-FU activity by the reduced folate leucovorin (5-formyl tetrahydrofolate [THF]), Ullman et al* reported that 20 mM leucovorin enhanced 5-FU cytotoxicity approximately fivefold in cultured leukemia cells. • Following on from this study, the antitumor activity of 5-FU/leucovorin was established in a number of studies of tumor cell lines, including those of human origin.
  43. 5-FU + Leucovorin • The preclinical data on the biomodulation of 5-FU cytotoxicity by leucovorin led to a large number of phase I and II clinical studies in the 1980s*
  44. • In 1989, study of Michael Poon and colleagues showed that there was a trend toward increased OS, RR and progression-free survival (PFS) with I.V. bolus 5-FU/leucovorin, compared with 5-FU alone in patients with mCRC. • The doses were as per Machover et al and Madajewicz et al
  45. • Machover et al* administered – 200 mg/m2 leucovorin using intravenous (I.V.) bolus and 370 mg/m2 5-FU in a 15-minute I.V. infusion daily for 5 days to patients with gastric cancer and mCRC, with courses repeated at 28-day intervals
  46. • Madajewicz et al* administered 500 mg/m2 leucovorin as a 2-hour infusion to patients with mCRC, with 5-FU up to a maximum of 750 mg/m2 given 1 hour after the leucovorin infusion; this schedule was repeated weekly for 6 weeks, followed by a 2-week rest period
  47. • Another important study, carried out by Petrelli et al*, demonstrated that the RR for 5-FU with high-dose leucovorin (48%) was significantly greater than that with 5-FU alone (11%) (overall p = .0009).
  48. • In a subsequent phase III study that compared 5-FU with high-dose or low- dose leucovorin with 5-FU alone, Petrelli* et al reported RRs of –  12% for 5-FU alone,  30% for 5-FU with high-dose leucovorin (P < .01), and  18.8% for 5-FU with low-dose leucovorin (P = not significant [NS]).
  49. • Most studies that evaluate the same dose of 5-FU with or without leucovorin find that both activity and toxicity are increased in the leucovorin arm
  50. Side effects of Leucovorin • Allergic reaction: rash, itching, facial flushing • Nausea and vomiting Facial flushing
  51. Just before 2000’s • Key developments in the early 2000s included the introduction of – Topoisomerase I inhibitor Irinotecan and Platinum containing agent Oxaliplatin as components of cytotoxic combination therapy for CRC
  52. • Irinotecan was first discovered and synthesized in Japan by Yakult Honsha Ltd in 1983 • It is a prodrug analogue (7-ethyl-10-piperidino-piperidino-carbonyloxy derivative) of the alkaloid camptothecin that is converted to the active metabolite SN-38 by liver carboxylesterases
  53. Side effects of Irinotecan • Diarrhea; two types early and late forms. • Early diarrhea: Occurring within 24 hours of receiving drug, accompanied by symptoms runny nose, increased salivation, watery eyes, sweating, flushing, abdominal cramping. • Late diarrhea: Occurring greater than 24 hours of receiving drug, usually peaks at about 11 days after treatment • Nausea and vomiting. • Weakness. • Low white blood cell count • Low red blood cell count
  54. • Oxaliplatin was also discovered in Japan at Nagoya City University by Yoshinori Kidani in 1976 by testing the antitumor activity of various platinum (II) complexes of 1,2-diaminocyclohexane isomers*
  55. Side effects of Oxaliplatin • Peripheral neuropathy - Numbness and tingling and cramping of the hands or feet often triggered by cold • Nausea and vomiting • Diarrhea • Mouth sores • Low blood counts • Fatigue • Loss of appetite
  56. • Saltz et al (2000)* found that treatment with bolus 5-FU/leucovorin and irinotecan (IFL) resulted in significantly – longer PFS (7.0 vs. 4.3 months; P = .004), greater RR (39% vs. 21%; P < .001), and longer OS (14.8 vs. 12.6 months; P = .04) • than 5-FU/leucovorin alone as first-line therapy for patients with mCRC.
  57. • In the Intergroup trial N9741*, the efficacy of FOLFOX (5-FU/leucovorin with oxaliplatin) was significantly better than that of IFL with regard to – OS (19.5 vs. 15.0 months, respectively; P < .0001) and RR (45% vs. 31%; P = .002).
  58. • The FOLFOX regimen was also associated with significantly lower rates of Toxicities* – severe nausea, vomiting, diarrhea, and febrile neutropenia than was the IFL regimen (p < .001).
  59. FOLFOX • Oxaliplatin and 5-FU are associated with side effects that, although not altogether overlapping, can be severe and include neurologic, hematologic, and gastrointestinal adverse events. • de Gramont et al of the GERCOR (Groupe d’Étude et de Récherche en Cancérologie Onco-Radiothérapic) cooperative in France have developed and successively conducted a series of oxaliplatin/5-FU–based regimens over the time
  60. • The series of FOLFOX (5-FU/LV/oxaliplatin) regimens, FOLFOX 1 to FOLFOX 7 were investigated in successive efforts to optimize the therapeutic ratio of 5- FU/LV and oxaliplatin, and these regimens have been tested in the first-line and salvage settings.
  61. • The method of 5-FU/LV administration is at the heart of the evolution of the FOLFOX strategies. • It has been well established that the incidence of gastrointestinal and hematologic toxicities is highly dependent on the dose and schedule of 5- FU/LV.
  62. • Moreover, although neurotoxicity is the primary dose-limiting side effect observed with oxaliplatin, myelosuppression and gastrointestinal toxicities are also observed when it is used in combination with 5-FU/LV
  63. Summary of the Evolution of FOLFOX • Before oxaliplatin was incorporated into 5-FU–based strategies, clinical evaluation showed that different methods of administering 5-FU with LV modulation, resulted in differing clinical efficacy as well as different spectrums and severity of toxicities
  64. • Randomized studies comparing bolus 5-FU with infusional schedules have consistently demonstrated higher response rates (RRs) with continuous 5-FU, albeit with minimal impact on overall survival (OS).
  65. • Administration of the infusional schedules of 5-FU has resulted in a significant reduction in the overall toxicity of this therapies specifically a marked decrease in the incidence of grade 3/4 neutropenia.
  66. • However, an increased incidence of hand-foot syndrome as well as gastrointestinal toxicity in the form of diarrhea have been observed with infusional 5-FU. • de Gramont et al subsequently developed a hybrid approach combining bolus 5-FU and infusional schedules of 5-FU.
  67. Varying the Oxaliplatin Dose with an Infusional Regimen of 5-FU/LV • The combination of 5-FU/LV and oxaliplatin was investigated initially using a chronomodulated strategy. • Levi et al evaluated - 5-FU 700 mg/m2 per day, LV 300 mg/m2 per day, and Oxaliplatin 25 mg/m2 per day, infused continuously but with the intensity modulated over the course of each day, for 5 days every 3 weeks * Levi F, Misset JL, Bienz S, et al. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid and oxaliplatin using an ambulatory multichannel programmable pump. Cancer 1992; 69:893-900
  68. • A phase III trial was subsequently conducted in the first-line setting comparing continuous nonchronologic administration directly with the chronomodulated schedule* • The chronomodulation strategy significantly improved the RR and safety profile of the regimen. * Levi FA, Zidani R, Vannetzel JM, et al. Chronomodulated versus fixed-infusionrate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. J Natl Cancer Inst 1994; 86:1608-1617
  69. • A 24-hour continuous infusion of 5- FU over 2 days allowed the dose of 5-FU to be increased to 2-fold higher in the dose administered via the chronomodulation schedule
  70. • Data comparing bolus versus infusional schedules of 5-FU show a slight benefit for infusions • These infusional schedules achieved widespread acceptance in Europe sooner than in the United States. • It was not until the advent of combination schedules of 5-FU plus other active agents that the benefits of infusional schedules, especially in terms of improved toxicity, asserted themselves in practice
  71. • In an initial feasibility study (FOLFOX1)* - oxaliplatin 135 mg/m2 was given over 2 hours on day 1 with LV 500 mg/m2 given on days 1 and 2 followed by a continuous 24-hour infusion of 5-FU 1500-2000 mg/m2 given on days 1 and 2 with cycles repeating biweekly (q 2 weekly) * de Gramont A, Gastiaburu J, Tournigand C, et al. Oxaliplatin with high- dose folinic acid and 5-fluorouracil 48 hours infusion in pretreated metastatic colorectal cancer. Proc Am Soc Clin Oncol 1994; 13:220 (Abstract #666)
  72. • The dose-limiting toxicities of this regimen were mucositis and neutropenia • The FOLFOX 3* regimen had reduced doses of oxaliplatin 85 mg/m2 versus FOLFOX 2 with oxaliplatin 100 mg/m2 in an effort to reduce the neurotoxicity observed with FOLFOX 2 * Andre T, Louvet C, Raymond E, et al. Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5- fluorouracil regimen. Ann Oncol 1998; 9:1251-1253
  73. • Although gastrointestinal, hematologic, and neurologic toxicities were reduced with this strategy, the RR decreased from 46% with FOLFOX 2 to approximately 20% with FOLFOX 3 in similar patient populations.
  74. Introducing Bolus Schedules of 5-FU Within the FOLFOX Regimen: FOLFOX4 • The FOLFOX4 regimen was developed in an effort to maintain the lower incidence of toxicity seen with FOLFOX2 and FOLFOX3, but regain the efficacy demonstrated in the earlier trials
  75. • To achieve this goal, boluses of 5-FU (400 mg/m2) were included on days 1 and 2, with a low-dose 5-FU infusion (600 mg/m2) administered over 22 hours on days 1 and 2 in combination with • oxaliplatin 85 mg/m2 (Day 1) • LV 200 mg/m2 (Day 1 and Day 2) every 14 days. • This regimen was then directly compared with FOLFOX3 in a randomized trial* *Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, flourouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999; 17:3560-3568
  76. • The FOLFOX4 regimen maintained a favorable gastrointestinal toxicity profile but resulted in a higher rate of neutropenia, which was believed to be largely caused by the 5-FU bolus *Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, flourouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999; 17:3560-3568
  77. • FOLFOX 4 was developed further in the first-line setting in phase III trials, in which it was found to be significantly more effective in terms of – median OS, time to tumor progression, and overall RR • compared with the bolus weekly schedule of IFL (irinotecan/5- FU/LV) *Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23-30
  78. Increasing the Oxaliplatin Dose and Simplifying the 5-FU/LV Regimen: FOLFOX6 • The FOLFOX6 regimen incorporated a higher dose of oxaliplatin (100 mg/m2) on day 1 with a simplified 5- FU/LV administration schedule: a single dose of LV (400 mg/m2) and bolus 5-FU (400 mg/m2) followed by a single continuous 46-hour infusion of 5-FU (2400-3000 mg/m2) every 2 weeks *Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer 1999; 35:1338-1342
  79. • In first- and second-line settings, treatment with FOLFOX 6 yielded overall RRs of 54% and 27%, respectively, and produced similar OS and PFS compared with previous FOLFOX regimens *Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer 1999; 35:1338-1342
  80. Maximizing Dose Intensity of Oxaliplatin: FOLFOX 7 • The FOLFOX 7 regimen was subsequently developed to maximize the dose intensity of oxaliplatin, and, according to de Gramont, this particular combination has emerged as the FOLFOX regimen with the optimal therapeutic ratio *Maindrault-Goebel F, de Gramont A, Louvet C, et al. High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7). Eur J Cancer 2001; 37:1000-1005
  81. • FOLFOX 7 incorporated the same simplified infusion schedule of 5-FU as was delivered with FOLFOX 6 but used a higher dose of oxaliplatin (130 mg/m2) • FOLFOX 7 resulted in a 42% RR and a median OS of 16.1 months, similar to the clinical efficacy observed earlier with high-dose oxaliplatin in FOLFOX 2
  82. • Because a higher dose of oxaliplatin was used in FOLFOX7, the incidence of gastrointestinal toxicities was slightly higher than had been previously observed with other FOLFOX regimens that used lower oxaliplatin doses.
  83. A Phase III Comparison of FOLFOX4 and FOLFOX7: OPTIMOX 1 • The FOLFOX 7 regimen was selected for further testing in the first-line setting in the OPTIMOX 1 trial in which it was compared directly with the FOLFOX4 regimen, which previously had yielded promising results in the first- and second-line settings. *de Gramont A, Cervantes A, Andre T, et al. OPTIMOX study: FOLFOX7/ LV5FU2 compared to FOLFOX 4 in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 2004; 23:251 (Abstract #3525)
  84. • To reduce the incidence of oxaliplatin-associated neurotoxicity, patients enrolled in the FOLFOX7 arm of the OPTIMOX trial received intermittent exposure to oxaliplatin: 6 cycles of FOLFOX7 followed by 12 cycles of 5-FU/LV and then reintroduction of oxaliplatin for an additional 6 cycles of FOLFOX7.
  85. Protocol Violation • Only 40% of the patients randomized to the FOLFOX7 arm received the scheduled reintroduction of FOLFOX7. • Moreover, depending on the particular treatment center, as many of 50% of patients who were randomized to receive FOLFOX4 received additional cycles of oxaliplatin beyond the 6 courses • In the multivariate analyses, patients who were reexposed to oxaliplatin had significantly improved median OS compared with those who received only 6 courses of treatment
  86. FOLFOX Conclusion • These all regimens used administration of 5-FU/LV and oxaliplatin, but they differed with respect to – oxaliplatin dose (85 mg/m2, 100 mg/m2, or 130 mg/m2), the schedule of infusional 5-FU (two 24- hour infusions or one 48-hour infusion), and the inclusion of bolus 5-FU
  87. • In the United States, the FOLFOX4 regimen has become the most widely used of these regimens. • However, there is growing evidence that the FOLFOX7 regimen, which incorporates high-dose oxaliplatin and a 48-hour infusion of 5-FU, yields higher RRs and reduced hematologic and neurologic toxicity compared with previous FOLFOX regimens, including FOLFOX4. FOLFOX Conclusion
  88. • The OPTIMOX study showed that FOLFOX7 and FOLFOX4 were similar in efficacy for the first-line treatment of advanced CRC. • The OPTIMOX study also demonstrated that reintroduction of oxaliplatin at the time of disease progression in patients who exhibit stable disease or a response after initial treatment was feasible FOLFOX Conclusion
  89. • The unfavorable toxicity profile of the IFL regimen led to the development of a regimen comprised of infusional IFL (FOLFIRI) – FOLFIRI Day 1: Irinotecan 180mg/m 2 IV over 30–90 minutes with: Day 1: Leucovorin 400mg/m 2 IV infusion to match duration of irinotecan infusion, followed by: Days 1–2: Fluorouracil 400mg/m 2 IV push day 1, then 1,200mg/m 2 /day × 2 days (total 2,400mg/m 2 over 46–48 hours) IV continuous infusion. Repeat cycle every 2 weeks.
  90. • The GOIM (Gruppo Oncologico Dell’Italia Meridionale) study* and the GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) crossover study* each showed similar efficacy for the FOLFIRI and FOLFOX regimens.
  91. • The GOIM* study reported RRs of 31% and 34% (P = NS), OS rates of 14 and 15 months (P = NS) for FOLFIRI and FOLFOX, respectively.
  92. • The GERCOR* study demonstrated – • OS rates of 21.5 months in patients allocated to FOLFIRI, and 20.6 months in those treated with FOLFOX (p = NS).
  93. FOLFOXIRI • The combination of – infusional 5-FU/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) was compared with FOLFIRI in 2 randomized, phase III trials.
  94. • Souglakos et al* reported no significant differences in OS, or RR between the 2 treatment regimens.
  95. • Falcone et al(2007)* showed a significantly – greater RR for patients treated with FOLFOXIRI than for those treated with FOLFIRI regimen (60% vs. 34%, respectively; P < .0001) significantly improved OS (22.6 vs. 16.7 months; P = .032) in the FOLFOXIRI arm compared with in the modified FOLFIRI arm, but at the cost of a significant (P < .001) increase in toxicity, in terms of increased grades of peripheral neurotoxicity (P < .001) and neutropenia (P < .001).
  96. • Orally administered 5-FU prodrugs were developed to provide a convenient alternative to treatment regimens requiring I.V. infusion of 5-FU. • An example of such an oral regimen is the combination of uracil and the 5- FU prodrug Tegafur (Uracil/UFT) in a 4:1 molar ratio
  97. • In a meta-analysis of 5 randomized controlled trials that compared UFT/leucovorin with bolus 5-FU/leucovorin, • Bin et al* reported that there were no significant differences in OS and RR between the 2 regimens; however, UFT/leucovorin had a significantly lower toxicity rate than bolus 5-FU/leucovorin (P < .001).
  98. • These findings were consistent with a pooled efficacy analysis from 2 phase III studies that compared Capecitabine (another oral 5-FU prodrug) with bolus 5-FU/leucovorin*
  99. Capecitabine • Capecitabine is a 5-FU precursor that is administered orally • It is absorbed intact through the gut and then activated by a series of enzymatic alterations • Some data suggest that thymidine phosphorylase levels are higher in tumor than in normal tissue. • This could, in theory, provide a degree of preferential intratumoral activation.
  100. • The major side effects of capecitabine appear to be palmar–plantar erythrodysesthesia, commonly called hand-foot syndrome, and to a lesser extent diarrhea. • The hand-foot toxicity is frequently a dose-limiting side effect
  101. • Phase III randomized clinical trials, performed both in the United States and Europe, have shown capecitabine as effective as intravenous 5-FU/leucovorin, and the side effect profile of capecitabine is less than that of 5- FU/leucovorin.
  102. • The CApecitabine, IRinotecan, Oxaliplatin (CAIRO) trial randomized 820 patients to sequential versus concurrent therapies. • In the sequential arm, first-line therapy was single-agent capecitabine. Upon failure, single-agent irinotecan was used, and then third-line therapy was Cape/Ox (as single-agent oxaliplatin is essentially inactive in 5-FU– refractory CRC). • The combination arm used Cape/Ox as first-line therapy and capecitabine and irinotecan as second-line therapy.
  103. • Median OS, was not statistically significantly different between the two arms (17.4 months for combination versus 16.3 months for the sequential arm, P = .33). • Dose-limiting toxicity (grade 3 or 4) was not significantly different between the two groups.
  104. • In the 1970s and 1980s, the antihelminthic drug levamisole attracted interest as a possible chemotherapeutic agent because of its putative immunomodulatory activity • In 1989, the North Central Cancer Treatment Group (NCCTG) reported that treatment with levamisole with 5-FU led to a significant reduction in cancer recurrence (P = .003) and a significant increase in OS (P = .03) when compared with no adjuvant therapy*
  105. • Interestingly, treatment with levamisole alone had no effect. • These findings led to the acceptance of only 5-FU with levamisole as the adjuvant therapy in the 1990s*
  106. Microsatellite Instability (MSI) • One form of genetic instability is manifested by changes in the length of repeated single- to six-nucleotide sequences known as DNA microsatellite sequences • Caused by a functional defect in DNA MMR • High levels of MSI (MSI-H) occur in about 15 % of colorectal carcinomas and are associated with right-sided colon carcinomas, frequently with poorly differentiated and mucinous histology but good prognosis
  107. • MSI is an established good prognostic factor • it also predicts a poor response to 5-FU Chemotherapy • Recent data suggest that mutation in BRAF is associated with MSI-H tumors and that colon carcinomas with both gene alterations have a significantly, worse prognosis in Stage III and IV Microsatellite Instability (MSI)
  108. KRAS and NRAS Mutation • KRAS and NRAS are important signaling intermediates in the growth receptor pathway, which Controls cell proliferation and survival • Normally, activated when EGFR binds EGF or similar growth factors • May be constitutively activated through mutation during colorectal carcinogenesis so that they continuously stimulate cell proliferation and prevent cell death
  109. • KRAS may be activated by somatic mutation in up to 40 % of colorectal carcinomas and NRAS in about 7 %. • Activation of either RAS gene is a modestly poor prognostic factor in Stage III and IV disease. • RAS activation predicts a poor response to monoclonal anti-EGFR antibody therapy in advanced colorectal carcinoma • KRAS mutation also may predict a poor response to anti-VEGF therapy in advanced colorectal carcinoma.
  110. BRAF Mutation • BRAF oncoprotein is a serine-threonine kinase that transmits cell growth and proliferation signalis from KRAS or NRAS to other enzymes. • Activating point mutation at BRAF may be detected in 6 -10% of colorectal carcinomas.
  111. • BRAF V600E mutation is associated with significantly worse prognosis. • MSI without BRAF is a good prognostic factor, whereas MSI-H with BRAF mutation portends slightly worse survival. • Blocks the effect of anti-EGFR antibodies on disease progression in Stage IV colorectal carcinoma. BRAF Mutation
  112. • In 1983 and 1984, John Mendelsohn and Gordon Sato and colleagues proposed epidermal growth factor receptor (EGFR) as a novel target for cancer therapy, based on observations that EGFR was frequently overexpressed in epithelial tumors and that monoclonal antibodies directed against EGFR inhibited the growth of cancer cells*
  113. • The anti-EGFR monoclonal antibodies – cetuximab and panitumumab were the first therapeutic agents targeted at a specific molecular pathology: EGFR-positive tumors expressing wild type Kirsten rat sarcoma viral oncogene homolog (KRAS)*
  114. • The efficacy of cetuximab in the treatment of patients with mCRC was evaluated in the CRYSTAL (Cetuximab Combined with Irinotecan in First- Line Therapy for Metastatic Colorectal Cancer) study* in which patients with EGFR-positive tumors were randomized to receive – • FOLFIRI alone or • FOLFIRI with cetuximab.
  115. • FOLFIRI with cetuximab as compared with FOLFIRI alone – • marginally improved PFS compared with (8.9 vs. 8.0 months, respectively; P = .048), • but there was no significant difference in OS between the 2 treatments (19.9 vs. 18.6 months; P = NS).
  116. • In a subset analysis of patients with wild type KRAS (63%), FOLFIRI with cetuximab as compared with FOLFIRI alone, significantly improved OS (23.5 vs. 20.0 months; P = .01), PFS (9.9 vs. 8.4 months; P = .001), and RR (57.3% vs. 39.7%; P = .001) • But, no significant difference in efficacy was evident in patients with mutant KRAS
  117. • In the PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) trial* patients were randomized to treatment with FOLFOX with or without panitumumab, regardless of EGFR or KRAS status.
  118. • In the subset with wild type KRAS (60% of the study population), panitumumab with FOLFOX compared with FOLFOX alone significantly improved – PFS (9.6 vs. 8.0 months, respectively; P = .02), but did not lead to a significant improvement in OS (23.9 vs. 19.7 months; P = NS).
  119. Bevacizumab • Bevacizumab, a MoAb targeting the vascular endothelial growth factor (VEGF) • Binds to VEGF, thereby substantially reducing the amount of circulating ligand and thus preventing receptor activation
  120. • The idea of targeting angiogenesis as an anticancer therapy was first proposed by Judah Folkman and colleagues in 1971. • However, it was not until 2004 that the pivotal Avastin/Fluorouracil 2107 phase III trial evaluated the humanized monoclonal antibody bevacizumab, which inhibits the action of vascular endothelial growth factor*
  121. • In this trial, patients were randomized to IFL with bevacizumab or IFL alone* • The addition of bevacizumab significantly improved– OS (20.3 vs. 15.6 months, respectively; P < .001), PFS (10.6 vs. 6.2 months; P < .001), and RR (44.8% vs. 34.8%; P = .004) as compared with IFL alone.
  122. • In another key trial, the Eastern Cooperative Oncology Group 3200 study it was found that OS (12.9 vs. 10.8 months, respectively; P < .0011), PFS (7.3 vs. 4.7 months; P < .0001), and RR (22.7% vs. 8.6%; P < .0001) were all significantly improved with bevacizumab and FOLFOX treatment compared with FOLFOX alone
  123. • In the FIRE-3* (FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer) trial, patients with wild type KRAS were randomized to receive first- line FOLFIRI with cetuximab or FOLFIRI with bevacizumab.
  124. • The primary end points of overall RR (62% vs. 58%, respectively) and PFS (10.0 vs. 10.3 months, respectively) were not significantly different in the 2 treatments arms. • However, FOLFIRI with cetuximab provided a statistically significant improvement in OS compared with FOLFIRI with bevacizumab (28.7 vs. 25.0 months, respectively; P = .017)*
  125. Ramucirumab • Ramucirumab is a monoclonal antibody that targets VEGF receptor 2 • In a clinical trial of patients receiving second-line FOLFIRI, the addition of ramucirumab versus placebo resulted in a median survival benefit of 1.6 months* *Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. PMID: 25877855.
  126. Aflibercept • Aflibercept is a fusion molecule containing the binding domains of VEGF receptors 1 and 2 bound to the human immunoglobulin (Ig)G Fc fragment, forming a VEGF trap molecule • Phase III VELOUR trial: second-line FOLFIRI plus aflibercept 4 mg/kg versus FOLFIRI plus placebo was s/o statistically significant OS benefit of 1.4 months • Aflibercept has not demonstrated benefit in conjunction with oxaliplatin based regimens
  127. Regorafenib • Orally administered small molecule multitargeted tyrosine kinase inhibitor • Regorafenib monotherapy can be considered as a standard care option for good performance status patients who have progressed through standard therapies.
  128. TAS-102 (Lonsurf) • TAS-102, another orally administered agent, is a combination of – trifluridine, a pyrimidine-based nucleic acid analogue, and tipiracil hydrochloride, an inhibitor of thymidine phosphoralase that serves to potentiate the trifluridine In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival* *Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. doi: 10.1056/NEJMoa1414325. PMID: 25970050
  129. Immunotherapy • Immunotherapy with immune checkpoint inhibitors that target the programmed death receptor 1 (PD-1; i.e. nivolumab, pembrolizumab), with or without immune checkpoint inhibitors that target a different checkpoint, cytotoxic T-lymphocyte antigen 4 (CTLA-4) may be beneficial for advanced high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) mCRC that has progressed following conventional chemotherapy.
  130. Evolution Of Chemotherapy
  131. Duration of Therapy • Controversy continues to exist regarding the optimal duration of chemotherapy for palliation of metastatic disease • Traditional practice for many years had been to continue chemotherapy until either – unacceptable toxicity, clinical deterioration, or disease progression.
  132. • Now, with patients typically living multiple years with metastatic CRC and with some treatments maintaining control for more extended periods of time, the need for patients to have breaks - often referred to as – • treatment holidays or • chemotherapy-free intervals [CFI] is greater Duration of Therapy
  133. Response Assessment • During chemotherapy, response is typically assessed using interval radiographic evaluation and by periodic assay of serum carcinoembryonic antigen (CEA) levels. • Although persistently rising CEA levels are highly correlated with disease progression, confirmatory radiologic studies should be obtained prior to a change in therapeutic strategy
  134. Thank You

Notas do Editor

  1.  antimetabolites. Specifically, floxuridine is a pyrimidine analog, 
  2. Elderly (70 years and older) patients, emergency operation and pts with medical complications have more chance of morbidity and mortality.( Stillwell et al).
  3. At this juncture, it is interesting to note that the antitumor activity of folic acid analogues, including aminopterin and amethopterin (methotrexate), was first demonstrated in 1948 by Sidney Farber and Louis Diamond in children with leukemia.23
  4. chronomodulated schedule - ability to deliver the therapeutic agent to a patient in a staggered profile
  5. mismatch repair - mmr
  6. vascular endothelial growth factor
  7. Vascular endothelial growth factor 
  8. The normal range for CEA is 0 to 2.5 nanograms per milliliter of blood (ng/mL)