Management Of Metastatic Carcinoma
Colon and Evolution of Chemotherapy
Dr Kartik Kadia
MMIMSR, Ambala

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

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.

• 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*

• 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.

• 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.

• 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.

TNM – 8th Edition Staging

TNM – 8th Edition Staging

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

Management
• Surgery
• Local therapies
• Chemotherapy

• 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

Synchronous Liver Only Or Lung Only
Metastases
Treatment modality is decided on basis of :
• Resectable or
• Unresectable

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

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

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

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

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.

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

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

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

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.

• 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)

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

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

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

• Issue of whether patients presenting with unresectable stage IV disease
should have their primary tumors resected or not has been the matter of
controversy

• 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.

Palliative Surgery
• Indicated in cases of –
impending obstruction,
perforation,
bleeding, or
pain.

Resection of cancer and primary anastomosis
-Diverting end colostomy with mucous fistula
-Bypass procedure
• Associated with high postoperative morbidity and mortality.
Palliative Surgery

Nonsurgical palliative options
• Intraluminal stent placement
Local palliation of an obstructing or nearly
obstructing tumor.

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

• 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

• 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

Evolution Of Chemotherapy in
Colorectal Carcinomas

• 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

• 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)

• 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

• 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.

• 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*

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

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.

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*

• 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

• 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

• 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

• 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).

• 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]).

• 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

Side effects of Leucovorin
• Allergic reaction:
rash,
itching,
facial flushing
• Nausea and vomiting
Facial flushing

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

• 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

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

• 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*

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

• 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.

• 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).

• 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).

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

• 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.

• 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.

• 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

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

• 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).

• 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.

• 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.

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

• 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

• 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

• 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

• 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)

• 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

• 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.

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

• 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

• 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

• 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

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

• 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

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

• 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

• 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.

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)

• 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.

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

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

• 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

• 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

• 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.

• 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.

• 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.

• 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).

FOLFOXIRI
• The combination of –
infusional 5-FU/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) was
compared with
FOLFIRI in 2 randomized, phase III trials.

• Souglakos et al* reported no significant differences in OS, or RR between the
2 treatment regimens.

• 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).

• 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

• 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).

• 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*

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.

• 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

• 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.

• 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.

• 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.

• 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*

• 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*

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

• 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)

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

• 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.

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.

• 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

• 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*

• 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)*

• 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.

• 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).

• 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

• 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.

• 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).

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

• 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*

• 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.

• 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

• 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.

• 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)*

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.

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

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.

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

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.

Evolution Of Chemotherapy

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.

• 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

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

Thank You