Highlights From: 27th Congress of the European Society for Medical Oncology Nice, France October 18–22, 2002

Meeting

Highlights Highlights From: 27th Congress of the European Society for Medical Oncology Nice, France October 18-22, 2002

Randomized Phase II Study of Bolus 5-Fluorouracil/ Leucovorin in Combination with Oxaliplatin or Irinotecan in Colorectal Cancer

higher RR than 5-FU/LV alone (53% vs. 16%, P < 0.001; 51% vs. 22%, P = 0.0001)7,8 and median time to disease progression (8.7 months vs. 6.1 months, P = 0.048; 9 months vs. 6.2 months, P =

Until recently, the standard of care in clinical practice for the treatment of advanced or metastatic colorectal cancer consisted of 5-fluorouracil (5-FU) and leucovorin (LV) with response rates (RRs) ranging from 11%-23%.1 The addition of irinotecan to 5-FU/LV (IFL) resulted in a higher RR and survival of patients with metastatic colorectal cancer.2,3 However, toxicity, particularly diarrhea with or without concomitant neutropenia, became a concern with IFL therapy. A number of new agents have been developed to try to improve the outcome of patients with advanced colorectal cancer. Oxaliplatin, a new third-generation platinum compound, has shown promising antitumor activity especially in combination with 5-FU/LV in colorectal cancer, with RRs ranging from 12% to 24% and a superior toxicity profile, with none of the renal or ototoxicities usually associated with cisplatin.4 Preclinical studies have shown that oxaliplatin/5-FU resulted in synergistic cytotoxic effects, and the addition of LV enhanced the cytotoxicity of this combination.5 Additionally, the administration of 5-FU as a 2-hour short exposure (bolus) after oxaliplatin appeared to overcome 5FU resistance in colorectal tumor cell lines.5,6 Several randomized phase III studies have shown that oxaliplatin in combination with 5-FU/LV resulted in a

Table 1: Results of Randomized Trials of Oxaliplatin in Combination with 5-Fluorouracil/ Leucovorin and/or Irinotecan in Metastatic Colorectal Cancer

Medical Writers: Kavita Maung, PhD, David Lee, PhD, Heather C. DeGrendele, PhD Reviewed by: Richard Schilsky, MD, Edward Chu, MD, Vinay K. Jain, MD, M. Sitki Copur, MD

Study

Giacchetti et al7

de Gramont et al8

Goldberg et al9

Tournigand et

al10

No. of Patients

Treatment

200

5-Fluorouracil/ Leucovorin plus Oxaliplatin every 3 weeks vs. 5-Fluorouracil/ Leucovorin every 3 weeks

420

795

226

0.0003; 8.8 months vs. 6.9 months, P = 0.0009; Table 1).7-10 Although a number of studies combining infusional 5-FU/LV with irinotecan and/or oxaliplatin are ongoing, there continues to be significant in-

Response Rate

Progression-Free Median Survival Survival Time (Months) (Months)

53%

8.7

19.4

16%

6.1

19.9

50.7%

9.0

16.2

22.3%

6.2

14.7

de Gramont FOLFOX4 regimen every 2 weeks

38%

8.8

18.6

Irinotecan/ 5-Fluorouracil/ Leucovorin every 2 weeks

29%

6.9

14.2

Oxaliplatin plus Irinotecan every 3 weeks

29%

6.7

16.5

56%

8.9

NR

57.5%

8.4

NR

5-Fluorouracil/ Leucovorin infusional de Gramont regimen plus Oxaliplatin every 2 weeks vs. 5-Fluorouracil/ Leucovorin every 2 weeks

FOLFOX6 followed by FOLFIRI every 2 weeks vs. FOLFIRI followed by FOLFOX6 every 2 weeks

The FOLFIRI regimen consisted of every-2-week irinotecan 180 mg/m2 day 1, folinic acid 200 mg/m2 day 1, 5-fluorouracil bolus 400 mg/m2 day 1 followed by 5-fluorouracil 46-hour continuous infusion 2.4-3 g/m2. FOLFOX4 consisted of oxaliplatin 85 mg/m2 on day 1 plus leucovorin 200 mg/m2 and 5-fluorouracil 400 mg/m2 bolus and 600 mg/m2 as a 22-hour infusion on days 1 and 2 every 2 weeks. FOLFOX6 consisted of every-2-week oxaliplatin 100 mg/m2 day 1 plus 5-fluorouracil 400 mg/m2 day 1, followed by 5-fluorouracil 46-hour continuous infusion 2.4-3 g/m2. Abbreviation: NR = not reported

140 • Clinical Colorectal Cancer November 2002

summarized below. This study included adult patients with histologically Arm I (n = 54) confirmed metastatOxaliplatin 100 mg/m2 I.V. day 1 ic colorectal cancer. R Leucovorin 250 mg/m2 Prior chemotherapy I.V. day 2 A 2 in the metastatic 5-Fluorouracil 1050 mg/m Stratified by: N I.V. bolus day 2 setting was not alD · Performance status every 2 weeks O · Previous adjuvant lowed. Patients were chemotherapy M stratified by performArm II (n = 54) I Irinotecan 200 mg/m2 ance status and prior Z I.V. day 1 adjuvant chemotherE Leucovorin 250 mg/m2 apy. Patients were I.V. on day 2 (n =108) 5-Fluorouracil 850 mg/m2 randomized to treatI.V. bolus day 2 ment with either oxevery 2 weeks aliplatin 100 mg/m2 intravenously (I.V.) terest in combining bolus 5-FU/LV with on day 1, LV 250 mg/m2 I.V. and 5-FU oxaliplatin or irinotecan. 1050 mg/m2 I.V. on day 2 or irinotecan Comella and colleagues from the 200 mg/m2 I.V. on day 1, LV 250 mg/m2 Southern Italy Cooperative Oncology I.V. and 5-FU 850 mg/m2 I.V. on day 2 Group are conducting a randomized study (Figure 1). 5-Fluorouracil was given as an comparing every-2-week dosing of oxali- I.V. bolus after oxaliplatin/LV in both platin to irinotecan when each is com- arms. Treatment cycles in each arm were bined with a single bolus of 5-FU/LV in repeated every 2 weeks. previously untreated metastatic colorectal One hundred eight patients (54 patients cancer patients.11 The initial phase II part in each treatment arm) of 130 had been of the study determined the efficacy and enrolled at the time of the interim analysafety of the oxaliplatin-based combina- sis. The median age was 62 years, and aption. The endpoint of the overall study proximately 30% of patients in each arm was to evaluate progression-free survival had received prior adjuvant chemothera(PFS) between the 2 treatment arms. The py. The liver was the dominant site of interim results of this study were present- metastatic disease in the majority of paed at the 27th European Society for Med- tients in each arm. ical Oncology (ESMO) Congress held in The oxaliplatin/5-FU/LV regimen apOctober 2002 in Nice, France, and are peared to give a somewhat higher RR compared to the IFL regimen (44% Table 2: Response and Survival: 5-Fluorouracil/Leucovorin vs. 32%, respecwith Oxaliplatin or Irinotecan tively), although Oxaliplatin/ Irinotecan/ these differences 5-Fluorouracil/ 5-Fluorouracil/ did not reach staLeucovorin Leucovorin (n = 52) (n = 53) tistical significance. The median Number of Patients (%) PFS was some32% 44% Overall Response Rate what longer in pa5 (9%) 5 (9%) Complete response tients on the oxali12 (23%) 18 (35%) Partial response platin/5-FU/LV arm compared to 12 (24%) 8 (15%) Stable disease patients on the IFL 58% 67% Control of Tumor Growth arm (9.6 months Survival vs. 7.1 months, respectively; P = 7.1 months 9.6 months Median progression-free survival 0.32; Table 2), but 57% 69% 6-Month progression-free survival this difference also Figure 1: Treatment Schema: Oxaliplatin/Leucovorin/ 5-Fluorouracil Versus Irinotecan/Leucovorin/ 5-Fluorouracil

did not reach statistical significance. Grade 3/4 neutropenia was observed in 55% of patients on the oxaliplatin/5FU/LV arm compared to 39% of patients on the IFL arm. As expected, grade 3/4 diarrhea was more commonly seen in patients on the IFL arm (24%) compared to 12% of patients on the oxaliplatin/5FU/LV arm. Oxaliplatin-associated grade 3 neurologic toxicity was observed in only 14% of patients on the oxaliplatin arm (Table 3). Conclusion: The interim results of this randomized phase II study suggest a higher RR and a longer PFS with oxaliplatin compared to irinotecan when combined with bolus 5FU/LV in previously untreated metastatic colorectal cancer. A previous randomized study by Tournigand and colleagues has suggested that both irinotecan and oxaliplatin might be equally effective when combined with infusional 5-FU/LV.10 Further studies will help clarify the optimal schedule of administration of 5-FU (infusional vs. bolus) and the choice of the partner drug (oxaliplatin vs. irinotecan).

Activity of Capecitabine/ Irinotecan and Capecitabine/ Oxaliplatin Combinations in Advanced Colorectal Cancer Capecitabine is an oral prodrug that is converted intracellularly to 5-FU in tumor cells and in the liver.12 Chronic oral dosing with capecitabine results in sustained intracellular exposure to 5-FU that mimics the continuous I.V. infusion of 5-FU. As a single agent, capecitabine has been shown to have a higher RR but a similar median survival to the I.V. Mayo Clinic 5-FU/LV regimen in patients with advanced colorectal cancer.13 In addition, capecitabine has a lower incidence of grade 3/4 neutropenia, nausea, and diarrhea compared to the Mayo Clinic regimen. Capecitabine is being studied in combination with oxaliplatin as well as irinotecan, and a number of phase II studies are under way worldwide. In a phase II trial by Twelves and colleagues, the combination of capecitabine plus oxaliplatin demonstrated an overall RR of

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MEETING HIGHLIGHTS Table 3: Grade 3/4 Toxicity: 5-Fluorouracil/Leucovorin with Oxaliplatin or Irinotecan

Figure 2: Treatment Schema: Capecitabine/Irinotecan Versus Capecitabine/Oxaliplatin

Oxaliplatin/ 5-Fluorouracil/ Leucovorin (n = 52)

Irinotecan/ 5-Fluorouracil/ Leucovorin (n = 53)

Neutropenia

55%

39%

Febrile neutropenia

13%

8%

Diarrhea

12%

24%

R A N D O M I Z E

Neurologic

14%

0

(n = 161)

Stomatitis

6%

6%

Fatigue

4%

2%

Hematologic Toxicities

Nonhematologic Toxicities

Stratified by: · Risk factors · Center

CAPIRI Capecitabine 1000 mg/m2 p.o. b.i.d. days 1-14 Irinotecan 80 mg/m2 days 1 and 8* Cycles repeated for 21 days until progression CAPOX Capecitabine 1000 mg/m2 p.o. b.i.d. days 1-14 Oxaliplatin 70 mg/m2 days 1 and 8 Cycles repeated for 21 days until progression

*Irinotecan was given at a dose of 100 mg/m2 days 1 and 8 to the first 40 patients. The irinotecan dose was then reduced to 80 mg/m2 days 1 and 8 to minimize toxicity.

8 (CAPIRI) or oxaliplatin 70 mg/m2 on days 1 and 8 thy was seen in the CAPOX arm but it (CAPOX). Cycles were repeated every reached grade 3 in severity in only 6% 22 days until disease progression (Fig- of the patients. Other nonhematologic ure 2). Due to a higher rate of early toxic toxicities were comparable between the death among the first 40 patients on the 2 arms and included diarrhea, nausea, CAPIRI arm (4 out of 40 patients vs. 0 vomiting, and infection (Table 5). No out of 40 patients in the CAPOX arm), patient in either arm developed grade 3 the dosage of irinotecan was lowered or 4 neutropenia, and grade 3/4 anemia from 100 mg/m2 to 80 mg/m2 days 1 and 8. and thrombocytopenia were rare. A total of 161 patients were treated, 79 with CAPIRI and 82 with CAPOX. Conclusion: Capecitabine in combination with eiThe median age was 63 and 62 years on the CAPIRI and CAPOX arms, respec- ther irinotecan or oxaliplatin demontively, and nearly all patients in each strated excellent activity against adgroup had a performance status (PS) of vanced colorectal cancer, with similar 0 or 1. At the time of this presentation, toxicity profiles. Capecitabine provides about two thirds of the patients were several advantages over the use of 5-FU, evaluable, and no significant difference including ease of administration and a in overall RR was seen in the CAPIRI more favorable toxicity profile with no arm versus the CAPOX arm (37.1% vs. 43.1%, respective- Table 5: Grade 3/4 Toxicity: Capecitabine/Irinotecan Versus Capecitabine/Oxaliplatin ly, P = 0.57; Table 4). With a Capecitabine/ Capecitabine/ median follow-up time of 10.8 Irinotecan Oxaliplatin months, PFS was also similar (n = 60) (n = 60) between the 2 arms (8.3 Hematologic Toxicities months vs. 6.0 months; P Table 4: Results: Capecitabine/Irinotecan 0 0 Neutropenia = 0.93). Versus Capecitabine/Oxaliplatin Initially, more treat3.2% 3.2% Anemia in Advanced Colorectal Cancer ment-related deaths (4 0 3.2% Thrombocytopenia Capecitabine/ Capecitabine/ out of 40 patients) were Irinotecan Oxaliplatin seen in the CAPIRI arm, Nonhematologic Toxicities (n = 54) (n = 58) but after the irinotecan 10.6% 13.5% Diarrhea 43.1% 37.1% Overall Response dose was reduced from 3.0% 6.0% Nausea 41.4% 37.0% Stable Disease 100 mg/m2 to 80 mg/m2 0 3.0% Vomiting on days 1 and 8, no addiDisease 15.5% 25.9% Progression tional treatment-related 6.0% 3.0% Infection deaths were seen. As exProgression-Free 6.0 months 8.3 months 6.1% 0 Sensory neuropathy Survival pected, sensory neuropa-

50% (6% complete response, 44% partial response) with low toxicity.14 In a phase I trial of capecitabine plus irinotecan, 8 out of 19 evaluable patients (42%) had a response.15 Based on these previous trials, Grothey and colleagues conducted a randomized phase II trial to compare the efficacy and toxicity of capecitabine/oxaliplatin to capecitabine/irinotecan in previously untreated patients with advanced colorectal cancer.16 The results of this study were presented at the 27th ESMO Congress held in October 2002 in Nice, France, and are discussed below. Patients were required to have inoperable and/or metastatic disease and an Eastern Cooperative Oncology Group performance status ≤ 2. No previous treatment for metastatic disease was allowed; however, patients could have had prior adjuvant therapy ≥ 6 months before entering the study. Patients were randomized to treatment with capecitabine 1000 mg/m2 twice daily days 1-14, combined with either irinotecan 100 mg/m2 on days 1 and

142 • Clinical Colorectal Cancer November 2002

MEETING HIGHLIGHTS grade 3/4 neutropenia and a lower incidence of diarrhea and mucositis. Based on the results of this study, the German Association of Medical Oncology group is conducting a randomized phase III trial comparing 24-hour infusion 5-FU/LV/oxaliplatin with capecitabine/oxaliplatin as first-line therapy for advanced colorectal cancer. Similar studies are also being considered by the US intergroup.

Epidermal Growth Factor Receptor Antibody Cetuximab in Combination with Irinotecan and 5-Fluorouracil/Leucovorin in Colorectal Cancer The epidermal growth factor receptor (EGFR) is a type I transmembrane tyrosine kinase receptor involved in the proliferation and differentiation of normal cells. Epidermal growth factor receptor expression is associated with poor treatment outcomes, disease progression, and patient survival.17 Epidermal growth factor receptor expression was found in 25%-77% of colorectal tumors,18 making it an important target in treatment of colorectal cancer. The anti-EGFR monoclonal antibody cetuximab has demonstrated antitumor activity and preclinical studies have shown that it can increase the activity of various chemotherapeutic agents.17 In clinical studies, cetuximab has been shown to be safe and active when administered with irinotecan to patients with irinotecan-refractory colorectal cancer, with 17% of patients achieving a partial response.19 These results suggested that cetuximab may improve on the activity seen with the regimen of IFL, which was shown in 2 phase III randomized trials to result in patient survivals of Figure 3: Treatment Schema: Cetuximab/ Irinotecan/5-Fluorouracil/ Leucovorin Cetuximab 250 mg/m2* Irinotecan 80 mg/m2 Leucovorin 500 mg/m2 I.V. over 2 hours followed by 5-Fluorouracil 1500 or 2000 mg/m2 as a 24-hour infusion cycle repeats

Week 1

2

3

4

5

*Loading dose cetuximab 400 mg/m2

6

7

8

14.8-17.4 months Table 6: Toxicity and Efficacy of Cetuximab/Irinotecan/ 5-Fluorouracil/Leucovorin in Metastatic compared with Colorectal Cancer 12.6-14.1 months with 5-FU/LV alone High-Dose Low-Dose Overall 5-Fluorouracil 5-Fluorouracil (P = 0.04).2,20 (n = 19) (n = 13) (n = 6) Lutz, Schöffski, Köhne, and col- Grade 3/4 Toxicities leagues have un3 (23%) 0 3 (16%) Diarrhea dertaken a phase 2 (15%) 1 (17%) 3 (16%) Skin rash I/II trial investigat9 (69%) 5 (83%) ing the safety and Overall Response Rate 14 (74%) efficacy of cetux1 (8%) 1 (17%) 2 (11%) Complete response imab plus irinote8 (62%) 4 (67%) 12 (63%) Partial response can and 5-FU/LV 3 (23%) 1 (17%) 4 (21%) Stable disease in EGFR+ metastatic colorectal cancer.21 Preliminary results were presented tients (62%) in the high-dose group had at the 27th ESMO Congress held in Oc- partial responses. The RR for the overall group was 74%. In addition, disease stabitober 2002 in Nice, France. The study enrolled patients with histo- lization occurred in 1 patient (17%) and 3 logically confirmed metastatic colorectal patients (23%) in the low-dose and highcancer with EGFR expression confirmed dose arms, respectively. by immunohistochemistry and a Karnofsky PS ≥ 60%. No prior chemotherapy Conclusion: was allowed except for 5-FU–based adjuThe results of this phase I/II study indivant therapy if completed > 6 months cate that cetuximab can be safely comprior to the inclusion. Previous treatment bined with irinotecan and 5-FU/LV for with monoclonal antibodies was not al- EGFR+ metastatic colorectal cancer. Dilowed. Patients received cetuximab 250 arrhea and skin rash have been the primg/m2/week (loading dose, 400 mg/m2) mary toxicities. The overall response rate plus irinotecan 80 mg/m2, LV 500 mg/m2, of 74% is encouraging. The low-dose 5and 5-FU 1500 mg/m2 (low-dose arm) or FU regimen in combination with cetux2000 mg/m2 (high-dose arm) weekly for 6 imab will be further investigated, and adof 7 weeks (Figure 3). ditional patients will be enrolled on the Twenty-one patients with EGFR ex- low-dose arm of this study. pression ≥ 1+ by immunohistochemistry were enrolled, 19 of whom were evaluable Gefitinib (Iressa™) Activity for toxicity and response. There were 6 patients in the low-dose 5-FU arm and 13 in Patients with Pretreated patients in the high-dose arm. The median Advanced or Metastatic age was 61 years (range, 36-68 years), and Colorectal Cancer The EGFR is overexpressed in a nummedian Karnofsky PS was 100% (range, ber of solid tumors, including 25%-77% 70%-100%). Diarrhea and skin rash were the pri- of tumors in patients with colorectal mary toxicities reported in cycle 1 (Table cancer.18 The specific overexpression of 6). Three patients on the high-dose arm EGFR on neoplastic tissue has provided (23%) and no patients on the low-dose a rationale for the development of spearm experienced a dose-limiting toxicity cific inhibitors that abrogate EGFR sigof grade 3/4 diarrhea. Grade 3/4 ac- naling and subsequent neoplastic efneiform skin rash occurred in 1 patient fects. Gefitinib (Iressa™) is an orally ac(17%) on the low-dose arm and in 2 pa- tive inhibitor of EGFR signal transductients (15%) on the high-dose arm. tion, which was shown in preclinical exThere was 1 complete response in both periments to block EGFR signal translow-dose and high-dose groups (17% and duction in cells that overexpress EGFR 8%, respectively; Table 6). Four patients as well as in some cell lines that overex(67%) in the low-dose group and 8 pa- press HER2.22

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MEETING HIGHLIGHTS Seymour and colleagues from the National Cancer Institute of Canada Clinical Trials Group undertook a phase I/II study of gefitinib in colorectal cancer patients.23 The results were presented at the 27th ESMO Congress held in October 2002 in Nice, France. This trial included a previously reported initial phase I dose-escalating portion in patients with various previously treated solid tumors.24 Epidermal growth factor receptor status was not assessed prior to inclusion. Patients received escalating doses of gefitinib 150800 mg/day for 28 days. Twenty-eight patients were enrolled in this portion of the trial, 4 of whom had colorectal cancer. Overall, the toxicity profile was mild and included skin rash and diarrhea. Based on these results, 750 mg/day of gefitinib was chosen for a phase II study in patients with colorectal cancer. The phase II portion of this trial included 27 patients with previously treated colorectal cancer and an Eastern Cooperative Oncology Group PS of 0-2.23 Treatment consisted of oral gefitinib 750 mg/day for 28 days. Biopsy was performed at baseline and after 28 days of treatment with gefitinib to assess for eviTable 7: Phase II Trial of Gefitinib in Colorectal Cancer: Adverse Events Toxicities

Number of Patients (%) (n = 27) Grade 1/2

Grade 3

Diarrhea

18 (67%)

4 (15%)

Nausea

16 (59%)

0

Vomiting

10 (37%)

0

Dry Skin

10 (37%)

0

Acneiform Rash

19 (70%)

1 (4%)

Fatigue

6 (22%)

2 (7%)

Table 8: Biological Effects of Gefitinib on Paired dence of activity. Most Tumor Samples (81%) of the 27 patients enrolled in this study had reNumber of Patients Tumor Marker/ ceived chemotherapy for Characteristic Increase Decrease No Change NA metastatic disease with 8 0 0 8 2 Ki67 (30%) having received adjuvant chemotherapy. Nine3 5 0 2 Nuclear Kip1 teen patients (70%) had re1 7 2 0 p-AKT ceived ≥ 2 chemotherapy 0 9 1 0 p-EGFR regimens. The 750 mg/day dose of 0 2 2 6 % Apoptotic Cells* gefitinib was not well toler% Change in 0 0 3 7 ated. Nine patients required Tumor Burden† dose reductions of gefitinib *Percent increase in apoptotic cells ranged from 2% to 34%. Percent decrease in primarily due to diarrhea (4 apoptotic cells ranged from 5% to 9%. †Percent increase in tumor burden ranged from 1% to 139%. Percent decrease in patients) and skin toxicity (3 tumor burden ranged from 9% to 19%. NA = not assessed; p-AKT = phosphorylated AKT; p-EGFR = patients). A grade 1/2 ac- Abbreviations: phosphorylated epidermal growth factor receptor neiform rash characteristic of gefitinib was seen in 19 patients, and a expression from 48% to 12%, as well as a grade 3 acneiform rash was seen in only 1 9% decrease in tumor burden following patient. Other grade 3 toxicities included treatment; 2 other patients demonstrated a fatigue (7%) and increases in serum crea- 19% decrease in tumor burden accompatinine (7%), bilirubinemia (11%), and ala- nied by impressive decreases in Ki67 exnine aminotransaminase (11%). There pression (from 20% to 5% and from 15% were no grade 4 toxicities reported (Table to 8%) and an increase in apoptotic cells (from 2% to 4% and from 5% to 28%). 7). No response was seen in the 24 evaluable patients. There was some evidence of Conclusion: antitumor activity, suggested by 8 patients The results of this phase I/II trial show who achieved stable disease with a medi- that single-agent gefitinib appears to have an duration of 2.2 months (range, 1.4-2.8 modest activity in patients with metastatic months). Ten of the 27 patients had serial colorectal cancer. A mild acneiform rash tumor biopsies fully evaluable for im- was the most common toxicity, although munohistochemical analysis (Table 8). A diarrhea was dose limiting. Previous trireduction in tumor burden was observed als have reported that the combination of in 3 of the 10 patients, with 1 patient hav- gefitinib with 5-FU/LV was well tolerated, ing a 9% decrease and 2 having a 19% de- and there did not appear to be any drug crease in tumor. Levels of the prolifera- interactions or enhanced toxicities seen.25 tion marker Ki67 decreased in 8 of the 10 To further this line of investigation, a patients, and the percentage of apoptotic number of trials are currently evaluating cells increased in 6 patients, suggesting gefitinib in combination with irinotecansome antitumor activity. Three patients and oxaliplatin-containing chemotherapy were of particular interest: 1 patient regimens. showed an increase in apoptotic cells from 5% to 39% and a decrease in Ki67

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