Deck 4

Question 1

<p>Is there a place for resection of primary?</p>

Answer 1

<p>The issue of whether patients presenting with unresectable stage IV disease should have their primary tumors resected has been the matter of some debate. Although such resections had been routinely performed in the past, more recent data suggest that such interventions are not required and may in fact be counterproductive.</p>

Question 2

<p>Give two studies about relevence of primary resection? What is the conclusion?</p>

Answer 2

<p>In a retrospective review, Poultsides et al. demonstrated that 93% of 233 patients never required surgical intervention on their primary tumors.NSABP C-10 trial prospectively addressed this question, treating 90 patients with unresectable stage IV disease and intact, asymptomatic primary tumors with initial medical management with FOLFOX-6 plus bevacizumab. A total of 12 patients (14%) experienced major morbidity due to the intact primary tumor.This study met its prespecified end points for acceptability of intial nonoperative management, and the investigators concluded that good performance status patients with asymptomatic primaries can be spared initial noncurative resection of their primaries.</p>

Question 3

<p>When surgery of primary is indicated?</p>

Answer 3

<p>Surgical intervention can be a very effective method of palliation and is often indicated in cases of impending obstruction, perforation, bleeding, or pain.</p>

Question 4

<p>What risk factors predicts decreased long-term survival after palliative surgery of primary(5)?</p>

Answer 4

<p>1. Elderly (70 years and older) patients with advanced local disease or extrahepatic metastases were at greatest risk for postoperative mortality. 2. Emergency operation and medical complications.3. Advanced nodal disease (N2) and poor tumor differentiation.4. Ascites. 5. ALP > 160 or PLT/lymphocyte ratio >162.</p>

Question 5

<p>What is important to remember about studies on chemotherapy in UrmCRC?</p>

Answer 5

<p>It is of paramount importance to keep in mind that virtually all of the clinical trials done in patients with metastatic disease were performed by design on patients who were in good overall general medical condition.It is not reasonable to extrapolate the results of these trials to patients who do not conform to these entry criteria. The likelihood of benefit in a poor performance status patient is substantially diminished, and the likelihood of a serious adverse event is greatly increased.</p>

Question 6

<p>What drug is the base of Chemotherapy?</p>

Answer 6

<p>5FU, remained the only drug available to treat CRC for almost four decades.</p>

Question 7

<p>What drug is used to biomodulate 5FU? What is the problem?</p>

Answer 7

<p>Only leucovorin remains in use today, and it is debatable whether this reduced folate truly contributes to the efficacy of 5-FU.</p>

Question 8

<p>What is the schedule of Roswell Park regimen?</p>

Answer 8

<p>LV 500 mg/ m2 over 2 h; 5-FU 500 mg/ m2 by bolus 1 h into LV infusion. Treatments given weekly for 6 consecutive wk, repeated every 8 wk.</p>

Question 9

<p>What is the schedule of de Gramont regimen?</p>

Answer 9

<p>LV 200 mg/ m2 over 2 h days 1 and 2, followed by bolus 5-FU 400 mg/ m2/ day 1 and 2, followed by 5-FU 600 mg/ m2 over 22 h days 1 and 2; cycle repeated every 14 d.</p>

Question 10

<p>What basic substance Irinotecan is based on?</p>

Answer 10

<p>Irinotecan is a semisynthetic derivative of Camptothecin, a plant alkaloid extracted from the wood of the Asian tree Camptotheca acuminate.</p>

Question 11

<p>What is the difference between Irinotecan &amp;amp; Campothecin?</p>

Answer 11

<p>Irinotecan possesses a bulky dipiperidino side chain linked to the camptothecinmolecule via a carboxyl-ester bond. This side chain provides solubility but greatly decreases anticancer activity.</p>

Question 12

<p>What metabolization Irinotecan go?</p>

Answer 12

<p>This side chain provides solubility but greatly decreases anticancer activity.Carboxylesterase, a ubiquitous enzyme with primary activity in the liver and gut, cleaves the carboxyl-ester bondto form the more active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38).</p>

Question 13

<p>What are the properties of SN-38 versus Irinotecan? What is the hesitation?</p>

Answer 13

<p>SN-38 is as much as 1,000-foldmore potent in inhibiting topoisomerase I (topo I) than irinotecan and is thus the predominant active form of the drug. Irinotecan is often considered to be a prodrug for SN-38; however, this concept may be a bit too simplistic,as achieved irinotecan concentrations may be several logs higher than those of SN-38.</p>

Question 14

<p>Waht is the mechanism of Camptothecin, irinotecan, and SN-38?</p>

Answer 14

<p>Camptothecin, irinotecan, and SN-38 function as inhibitors of topo I. Topo I is a nuclear enzyme that aids in DNA uncoiling for replication and transcription. When topo I binds to DNA, it causes a reversible single-stranded break in the DNA, allowing the intact strand to pass through the break to relieve torsional stress on the coiled helix, and then reseals the break. Irinotecan and SN-38 stabilize these single-stranded breaks. Although the stabilized breaks do not cause irreversible damage, the collision of replication forks with open single-strandedbreaks results in double-stranded breaks, leading to lethal DNA fragmentation.</p>

Question 15

<p>What (simplified) FOLFIRI regimen include?</p>

Answer 15

<p>Irinotecan 180 mg/m2 over 90 min; LV 400 mg/m2 concurrently with irinotecan (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2, followed by 5-FU 1,200 mg/m2/d times 2 d (2,400 mg/m2 infusion over 46–48 h). Cycle repeated every 14 d.</p>

Question 16

<p>Which study showed first the effectiveness of FOLFIRI in mCRC?</p>

Answer 16

<p>The Bolus, Infusional, or Capecitabine with Camptosar- Celecoxib (BICC-C) trial is the only trial to directlycompare weekly bolus IFL to FOLFIRI.</p>

Question 17

<p>What was the design and results of The Bolus, Infusional, or Capecitabine with Camptosar- Celecoxib (BICC-C) trial?</p>

Answer 17

<p>This trial utilized a modified bolus IFL schedule, giving treatment on days 1 and 8, repeated on a 3-week cycle. This modified IFL was compared to FOLFIRI as well as to capecitabine/irinotecan. The first phase of this trial (430 patients) confirmed the superior safety and efficacy of FOLFIRI over IFL (median progression-free survival, 7.6 months for FOLFIRI versus 5.8 months for IFL; P =.007) and over capecitabine/irinotecan (progression-free survival, 5.7 months; P = .003).</p>

Question 18

<p>What is the most prominent s/e of Oxaliplatin?</p>

Answer 18

<p>Neurotoxicity. This neurotoxicity manifested asparesthesias and dysesthesias of the hands, feet, perioral region, and throat. Pharyngolaryngeal dysesthesia, asensation of choking without overt airway blockage, was described as well.</p>

Question 19

<p>What is FOLFOX-4 regimen?</p>

Answer 19

<p>Oxaliplatin 85 mg/m2 over 2 h; LV 200 mg/m2 concurrently with oxaliplatin (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2,followed by 5-FU 600 mg/m2 infusion over 22 h. Oxaliplatin given day 1 only. All other medicines given days 1 and 2. Cycle repeated every 14 d.</p>

Question 20

<p>What is FOLFOX-6 regimen?</p>

Answer 20

<p>Oxaliplatin 100 mg/m2 over 2 h; LV 400 mg/m2 concurrently with oxaliplatin (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2, followed by 5-FU 1,200 mg/m2/d times 2 d (2,400 mg/m2 infusion over 46–48 h). Cycle repeated every 14 d.</p>

Question 21

<p>What is Modified FOLFOX-6?</p>

Answer 21

<p>Oxaliplatin 85 mg/m2 over 2 h; LV 400 mg/m2 concurrently with oxaliplatin (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2, followed by 5-FU 1,200 mg/m2/d times 2 d (2,400 mg/m2 infusion over 46–48 h). Cycle repeated every 14 d.</p>

Question 22

<p>Which FOLFOX regimen is used mostly today?</p>

Answer 22

<p>Modified FOLFOX-6</p>

Question 23

<p>What is the rule of high doses of calcium and magnesium for Oxaliplatin neuropathy?</p>

Answer 23

<p>It had been previously hypothesized that administration of high doses of calcium and magnesium with oxaliplatin would be protective against neurotoxicity, but a definitive trial has now demonstrated that this is not the case.</p>

Question 24

<p>What Studies show about FOLFOX versus FOLFIRI as first line for mCRC?</p>

Answer 24

<p>Tournigand et al. reported a phase III trial of FOLFOX-6 versus FOLFIRI. This trial utilized identical simplified LV5FU2 schedules, with the only variable beingoxaliplatin or irinotecan. All patients were planned to crossover to the other regimen at time of progression, and the primary end point was time to tumor progression after both chemotherapy regimens.the results show a striking consistency between regimens, suggesting that use of either FOLFOX-6 or FOLFIRI in first-line treatment isacceptable.A somewhat larger trial of 360 patients randomized to FOLFOX-4 versus the equivalent FOLFIRI schedule, utilizing the same LV5FU2 dose and schedule in each arm, again shows comparable efficacy data, with differing and predictable toxicity profiles.</p>

Question 25

<p>What were the results of study N9741?</p>

Answer 25

<p>The efficacy results of N9741, however, were statistically significant and showed superior outcome for the patients randomized to FOLFOX-4, as compared to those randomized to either IFL (Bolus w/o 5-FU infusion component) or IROX (Irinotecan &amp;amp; Oxaliplatin bolus w/o 5FU or LV), in terms of response rate, time to tumor progression, and OS. Toxicity for FOLFOX-4 was also superior for virtuallyall parameters, except of course neurotoxicity. The results of the IROX arm did not statistically significantly differ from those of the IFL arm in terms of toxicity, response, or time to tumor progression; however, survival was borderline statistically significantly better in the IROX arm than the IFL arm.</p>

Question 26

<p>What help to decide between FOLFOX/FOLFIRI as first line for mCRC?</p>

Answer 26

<p>Whether to use an irinotecan-based or oxaliplatin-based combination in first-line treatment of goodperformance status patients can be considered a matter of patient preference, and discussion of the differing toxicity profiles is appropriate to help individuals decide.</p>

Question 27

<p>What was the design of OPTIMOX study?</p>

Answer 27

<p>In this trial, patients were randomly assigned to receiveeither standard FOLFOX-4 until progression or 12 weeks of FOLFOX-7 (130 mg/m2 dose of oxaliplatin), followed by planned cessation of oxaliplatin and continuation of the LV5FU2. As designed, the study called for a reintroduction of oxaliplatin after 6 months of LV5FU2, although this actually occurred in the minority of patients and outcomes were superior in those patients in whom reintroduction of oxaliplatin occurred.The primary end point was duration of diseasecontrol, the time from initiation of treatment until either progression through all agents (including failure afterreintroduction of oxaliplatin if this was done), or death.</p>

Question 28

<p>What where the results of OPTIMOX study? what are the consequences?</p>

Answer 28

<p>Duration of disease control as well as progression-free survival and OS were not statistically significantly different between the two arms. As anticipated, toxicity, including neurotoxicity, was substantially reduced in the OPTIMOX arm.This OPTIMOX strategy of plannedinterruption of oxaliplatin can be considered a standard care option in metastatic disease. It is important to discuss plans for such planned interruptions with patients at the beginning of therapy so that they will not be surprised or alarmed at the removal of one of the drugs.</p>

Question 29

<p>What is FOLFOXIRI protocol? what study on it showed?</p>

Answer 29

<p>Several groups are also exploring the use of “triple therapy” with oxaliplatin, irinotecan, and 5-FU/leucovorin (FOLFOXIRI). A randomized phase III trial conducted in Italy reported that FOLFOXIRI istolerable and offers a modest survival benefit over FOLFIRI.</p>

Question 30

<p>What about CAPOX insted of FOLFOX?</p>

Answer 30

<p>Trial comparing FOLFIRI to capecitabine/irinotecan suggested inferior outcome for the capecitabine-containing regimen.However, a large randomized trial has now compared Cape/Ox versus FOLFOX. The study also had a two-by-two randomization to with or without bevacizumab (discussed subsequently). This trial demonstrated the Cape/Ox regimen to be noninferior to FOLFOX, and each had acceptable toxicity, indicating that Cape/Ox is an acceptable alternative to FOLFOX.</p>

Question 31

<p>For whom the CAPOX regimen is suitable?</p>

Answer 31

<p>It should be noted that the Cape/Ox regimen requires a motivated, reliable patient who will be able to take multiple pills of oral medication on a complex schedule, even in the setting of potentially emetogenic oxaliplatin.</p>

Question 32

<p>What was the purpose &amp; design of OPTIMOX-2 study? What where the results?</p>

Answer 32

<p>The idea of planned early cessation of all chemotherapy was investigated in the OPTIMOX-2 trial. A total of 202 patients with previously untreated metastatic CRC were treated. All patients received six cycles of modified FOLFOX-7 followed by either continued LV5FU2 until progression or a complete cessation of all chemotherapy (a CFI). Patients on both arms were planned to receive retreatment with FOLFOX following tumor progression.The results of this study did not support the use of this planned, early interruption in therapy, as the medianduration of disease control, progression-free survival, and OS were all inferior in the arm with the early planned CFI.</p>

Question 33

<p>What are the conclusions from OPTIMOX-2 study?</p>

Answer 33

<p>This should not be misconstrued as evidence that CFIs are contraindicated but rather that early planned CFIsfor all patients is not an appropriate strategy. The authors suggest that this study indicates there are no pretreatment parameters that can identify a priori those patients who can successfully benefit from a CFI. Thus, specific decisions regarding use and timing of CFIs cannot be made in advance of starting treatment; rather, clinical judgment must be exercised in deciding on treatment interruptions for CFIs in responding patients after a favorable response.</p>

Question 34

<p>What retrospective analysis of two OPTIMOX trials showed?</p>

Answer 34

<p>In a retrospective review of 822 patients in the two OPTIMOX studies, after excluding thosepatients who had early progression within the first 3 months of treatment as well as those who underwent complete gross resection of metastatic disease within 3 months of stopping chemotherapy, Perez-Staub et al.noted that there was no indication of a detriment in survival when comparing those patients who took a CFI versus those who did not.In fact, in this retrospective, nonrandomized analysis, the median survival was 37.5 months in patients who had a CFI versus 21.2 months in matched patients who did not have a CFI. Of note, median OS of patients who stopped chemotherapy earlier than 3 months was 24 months, whereas it was 42 months when a CFI was taken between 3 and 9 months into therapy, and 44 months when a CFI was taken later than 9 months intochemotherapy.</p>

Question 35

<p>What are the median time to rechallenge, response rate &amp;amp; Median survival for rechallenge with 5-FU after a planned treatment interruption according to study who inspected this question?</p>

Answer 35

<p>Median time to rechallenge was 11.7 months. A total of17% of patients had an objective response to rechallenging. Median survival for the group was 14.8 months.</p>

Question 36

<p>What was the design and results of a study about secession of 2nd line Irinotecan?</p>

Answer 36

<p>A total of 333 patients entered into a trial to receive 24 weeks of irinotecan. Patients who remained in the study at the end of that time were to be randomized to either continue treatment or to stop therapy. Of the 333 patients, most came off the study due to progression or toxicity before reaching the 24-week mark. A total of 55 patients with responding orstable disease agreed to randomization. Although the numbers available for comparison were small, there were no differences between the arms in progression-free survival or OS or were there differences in quality-of-life scores.</p>

Question 37

<p>What was the purpose and design of CAIRO study?</p>

Answer 37

<p>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 assecond-line therapy.</p>

Question 38

<p>What were the results in CAIRO?</p>

Answer 38

<p>The primary end point, 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). PFS (1st line) &amp;amp; RR were statistically significantly better on combination arm.</p>

Question 39

<p>What was the design of FOCUS study? What was the main result?</p>

Answer 39

<p>Arm A(sequential): LV5FU2 --> IrinotecanArm B: LV5FU2 --> FOLFOX or FOLFIRIArm C: FOLFOX or FOLFIRIThe primary end point, median OS: -. Arm A was 13.9 months. -. Arm B, survival was 15.0 months for irinotecan and 15.2 months for oxaliplatin. -. Arm C had a median OS of 16.7 months for the FOLFIRI patients and 15.4 months for those treated with FOLFOX.Only the difference between arm A and the irinotecan arm of arm C reached statistical significance (P = .01).</p>

Question 40

<p>What is the conclusion from CAIRO &amp; FOCUS studies?</p>

Answer 40

<p>Taken together, the CAIRO and FOCUS trials provide a strong argument that not all patients with unresectable metastatic disease require exposure to the toxicity of combination therapy and that initial use of fluorinated pyrimidine alone in patients with previously untreated metastatic CRC is a treatment alternative that needs to be carefully considered.</p>

Question 41

<p>What is the mechanism of AVASTIN?</p>

Answer 41

<p>Bevacizumab is a humanized monoclonal antibody that binds to VEGF, thereby substantially reducing the amount of circulating ligand and thus preventing receptor activation.</p>

Question 42

<p>What was the first trail in AVASTIN on CRC? What were the results and problem?</p>

Answer 42

<p>The first trial of bevacizumab in CRC was amodest-sized, three-arm, randomized phase II trial in which a total of 104 patients were randomly assigned to either one of two different doses levels of bevacizumab (5 mg/kg or 10 mg/kg) plus weekly 5-FU/leucovorin or to 5-FU/leucovorin alone.The response rate, time to tumor progression, and OS were superior in the 5-FU/leucovorin with 5 mg/kg bevacizumab arm.Despite the small size and limited statistical power of this study, this result would serve as the basis for design of the pivotal phase III trial of bevacizumab in CRC.</p>

Question 43

<p>What was the design of phase 3 trail in AVASTIN on CRC? What were the results?</p>

Answer 43

<p>A three-arm trial was designed that contained (1) 5-FU/leucovorin/bevacizumab, (2) IFL/bevacizumab, and (3) IFL/placebo (the control arm).In the final efficacy analysis, the IFL/bevacizumab cohort experienced superior outcome compared to theIFL/placebo group in response rate (45% versus 35%, P < .003), progression-free survival (10.6 versus 6.2months, P < .00001), and OS (20.3 versus 15.6 months, P = .00003)</p>

Question 44

<p>What was the design of ECOG-3200 on AVASTIN?</p>

Answer 44

<p>evaluate the use of bevacizumab in the second-line setting. This trial randomized patients who had failed irinotecan and 5-FU but were naïve to bevacizumab to one of three arms: bevacizumab/FOLFOX, FOLFOX alone, or bevacizumab. The investigators chose to investigate a 10 mg/kg bevacizumab dose. Overall, a modest but statistically significant improvement in median OS was demonstrated for FOLFOX-4 with bevacizumab versus FOLFOX-4 alone (12.5 versus 10.7 months, P = .0024), and grade 3 or 4 toxicities were not increased. The bevacizumab-alone arm had substantially inferior progression-free survival and an investigator adjudicated response rate of 3%.</p>

Question 45

<p>What trail conducted on first line AVASTIN+FOLOFX? What were the results? </p>

Answer 45

<p>NO16966 trial directly addressed the question of front-line bevacizumab plus oxaliplatin-based therapy.

Although the study did show a statistically significant progression-free survival advantage for the
addition of bevacizumab (9.4 versus 8.0 months for chemotherapy with bevacizumab versus chemotherapy with placebo, respectively; HR, 0.83; P = .003), this difference was more modest than the 4.4-month progression-free survival difference seen in the initial bevacizumab with IFL front-line trial. OS improvement with bevacizumab approached, but did not reach, statistical significance (21.3 versus 19.9 months; HR, 0.89; P = .077).</p>

Question 46

<p>What was the grade 3 hypertension in the bevacizumab/IFL arm than in the placebo/IFL arm?</p>

Answer 46

<p>11% versus 2%.</p>

Question 47

<p>What are two serious a/e of AVASTIN?</p>

Answer 47

<p>GI perforations and arterial thrombotic events.</p>

Question 48

What risk factors exist to GI perforation?

Answer 48

No clear risk factors for these perforations could be identified.
Concerns have been expressed by some clinicians about the possibility of needing to remove an asymptomatic primary colorectal tumor in a patient with synchronous stage IV disease before using bevacizumab out of an unsubstantiated fear that the primary will put the patient at risk for perforation. At present, there are no data to support this assumption, and surgery for an asymptomatic primary
tumor in a stage IV patient is not routinely indicated, regardless of whether there are plans to use a bevacizumab containing chemotherapy regimen.

Question 49

What is the incidence arterial thrombotic events related to AVASTIN? is there risk factors? When the risk is higher?

Answer 49

The observed incidence of these events was 2.5% in the nonbevacizumab-containing control arms versus 5.0% in the bevacizumab-containing experimental arms.

It was noted that patients who had histories of cardiovascular or atherosclerotic disease appeared to be at greater risk for increased bevacizumab-related arterial thrombotic complications.

In addition, a further analysis of these events suggested that the risk was essentially linear over
time, indicating that the risk of a new arterial thrombotic event was the same in earlier versus later months of
exposure.

Question 50

What is the rate of Fistula formation? What are the common locations? average time to appear? What is the best treatment?

Answer 50

Ganapathi et al.420 reports a 4.1% incidence of this problem in a review of 222 patients with metastatic CRC.
Two-thirds were perineal or anal with the remainder colovesicular, occurring an average of 3.9 months after
initiation of treatment. Cessation of bevacizumab led to fistula healing in nearly all cases.

Question 51

What study show the efficacy of FOLFOXIRI+AVASTIN? What was the design and results?

Answer 51

Loupakis et al. randomized 508 patients with previously untreated metastatic CRC to receive either FOLFOXIRI plus bevacizumab or FOLFIRI plus bevacizumab.
All patients had an excellent performance status (mostly ECOG 0).

The median progression-free survival was 12.1 months versus 9.7 months, respectively (P = .003). FOLFOXIRI was also superior in terms of response rate (65% versus 53%, P = .006). OS was improved from 25.8 months to 31.0 months with a P value that just missed
statistical significance (P = .054).

Question 52

What question addressed ML18147 trial? what were the results?

Answer 52

In this trial, 820 patients who had progressed through a first-line, bevacizumab-containing regimen were assigned to a non–cross-resistant chemotherapy regimen and then randomized to receive bevacizumab with this second-line chemotherapy or not. The arm receiving bevacizumab showed a modest but statistically significant survival benefit of 1.4 months.

Question 53

What is the mechanism and survival benefit of Aflibercept? and what is of Ramucirumab?

Answer 53

Aflibercept is a fusion molecule containing the binding domains of VEGF receptors. Aflibercept binds all human VEGF A isoforms, VEGF B, and placental growth factor with greater affinity than the native receptors for these ligands.
The findings of the VELOUR and TML trials show striking similarities to one another. Each utilized an anti- VEGF strategy in second-line treatment in conjunction with active chemotherapy, and each shows a 1.4-month survival benefit.

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.