Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer (MOSAIC Trial)

Design

Phase 3, multicenter, randomized, comparative study

N= 2,246

Objective

To evaluate the efficacy of treatment with fluorouracil plus leucovorin (FL) plus oxaliplatin in the postoperative adjuvant setting

Study Groups

FL (n= 1,123)

FL + oxaliplatin (n= 1,123)

Inclusion Criteria

Age 18 to 75 years; undergone complete resection of histologically proven stage II (T3 or T4,N0,M0) or stage III (any T,N1 or N2,M0) colon cancer; Karnofsky performance-status score of at least 60; carcinoembryonic antigen level of less than 10 ng per milliliter; absence of prior chemotherapy, immunotherapy, or radiotherapy; adequate blood counts and liver and kidney function

Exclusion Criteria

Not disclosed

Methods

Eligible patients were randomized to receive either FL alone or with oxaliplatin. Each FL cycle consisted of a 2-hour infusion of 200 mg of leucovorin per square meter of body-surface area followed by a bolus of 400 mg of fluorouracil per square meter and then a 22-hour infusion of 600 mg of fluorouracil per square meter given on 2 consecutive days every 14 days, for 12 cycles. The FL+oxaliplatin group received the same FL regimen plus a two-hour infusion of 85 mg of oxaliplatin per square meter on day 1, given simultaneously with leucovorin, with the use of a Y infusion device. Outpatient administration of infusions was completed using disposable infusion pumps. 

Dose reductions of treatment interventions were based on the worst adverse effects observed during the previous cycle. The dose of oxaliplatin was reduced to 75 mg/m² in the event of persistent paresthesias, temporary painful paresthesias, or functional impairment, and was discontinued in cases of persistent painful paresthesias or functional impairment. Together with reductions in the dose of oxaliplatin, the bolus dose of fluorouracil was reduced to 300 mg/m² and the infusion to 500 mg/m² in the event of grade 3 or 4 neutropenia or thrombocytopenia (or both), diarrhea, stomatitis, or other drug-related adverse effects of grade 3. Only the dose of fluorouracil was scheduled to be reduced in the event of skin-related adverse effects of grade 3 or 4. Treatment was delayed by up to three weeks until patients recovered from various adverse effects, the neutrophil count exceeded 1500 per cubic millimeter, and the platelet count exceeded 100,000 per cubic millimeter. In the event of cardiac or neurocerebellar adverse effects or grade 3 or 4 allergic reactions, chemotherapy was discontinued.

Duration

Median follow-up: 37.9 months

Outcome Measures

Primary: disease-free survival, defined as the time from randomization to relapse or death, whichever occurred first

Secondary: rates of relapse and death; adverse events

Baseline Characteristics

FL+oxaliplatin (n= 1,123)

FL (n= 1,123)

Median age, years

Female

Karnofsky performance score

< 60

60-70

80-100

0.4%

13.4%

86.2% 

0.4%

11.9%

87.6% 

Disease stage

II

III

40.2%

59.8%

39.9%

60.1%

Depth of invasion

T2

T3

T4

Unknown

4.5%

76.0%

19.0%

0.5%

4.8%

75.9%

18.5%

0.8%

Disease description of overall population

Bowel obstruction

Perforation

Histologic appearance

Well differentiated

Poorly differentiated

Unknown

17.9%

6.9%

83.2%

12.6%

4.2%

19.3%

6.9%

81.4%

13.2%

5.4%

Patients with stage III disease

Number of nodes involved

1-4

>4

Unknown

44.4%

15.1%

0.2%

45.7%

14.2%

0.2%

Patients with stage II disease

T4

Number of lymph nodes examined

< 10

≥ 10

Bowel obstruction

Perforation

Histologic appearance

Well differentiated

Poorly differentiated

Unknown

18.6%

33.7%

65.4%

15.7%

8.4%

85.4%

10.4%

4.2%

19.4%

33.3%

65.6%

19.4%

9.6%

84.4%

9.4%

6.3%

Intervention

Median number of cycles

Percent who received all planned 12 cycles

12

74.7%

12

86.5%

Median Follow-up, months

37.9 (27 to 54)

37.8 (27 to 54)

In the FL+oxaliplatin group, the median dose of oxaliplatin was 36.5 mg/m2/week with 85.9% of the planned dose actually administered. The fluorouracil dose administered was 97.7% and 84.4% of the planned dose for the FL group and FL+oxaliplatin group respectively.

Results

Endpoint

FL+oxaliplatin (n= 1,123)

FL (n= 1,123)

p-Value

Probability of disease-free survival at 3 years (95% confidence interval [CI])

Event, n

Relapse^¶

Metastasis

Second colorectal carcinoma

Local relapse

237 (21.1%)

208 (18.5%)

169 (15%)

6 (0.5%)

38 (3.4%)

293 (26.1%)

279 (24.8%)

229 (20.4%)

9 (0.8%)

51 (4.5%) 

--

--

--

--

--

Death without relapse

Death at primary analysis cutoff date

Number with stage III disease

133

104

146

119

--

-- 

Adverse Events

Paresthesia^§

All grades

Grade 3

Grade 4

Neutropenia

All grades

Grade 3

Grade 4

Neutropenia with fever or infection

All grades

Grade 3

Grade 4

Thrombocytopenia

All grades

Grade 3

Grade 4

Anemia

All grades

Grade 3

Grade 4

Nausea

All grades

Grade 3

Grade 4

Diarrhea

All grades

Grade 3

Grade 4

Vomiting

All grades

Grade 3

Grade 4

Stomatitis

All grades

Grade 3

Grade 4

Skin^†

All grades

Grade 3

Grade 4

Alopecia^‡

All grades

Grade 3

Grade 4

Allergic reaction

All grades

Grade 3

Grade 4

Thrombosis or phlebitis

All grades

Grade 3

Grade 4

92%

12.4%

N/A

78.9%

28.8%

12.3%

1.8%

1.4%

0.4%

77.4% 

1.5%

0.2%

75.6%

0.7%

0.1%

73.7%

4.8%

0.3%

56.3%

8.3%

2.5%

47.2%

5.3%

0.5%

41.6%

2.7%

0

31.5%

1.4%

0.6%

30.2%

N/A

N/A

10.3%

2.3%

0.6%

5.7%

1.0%

0.2%

15.6%

0.2%

N/A

39.9%

3.7%

1.0%

0.2%

0.1%

0.1% 

19%

0.2%

0.2%

66.9%

0.3%

0

61.1%

1.5%

0.3%

48.4%

5.1%

0.3%

24%

0.9%

0.5%

39.6%

2%

0.2%

35.5%

1.7%

0.7%

28.1%

N/A

N/A

1.9%

0.1%

0.1%

6.5%

1.7%

0.1%

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

0.34

0.05

0.28

<0.001

0.48

^¶The same patient could have been counted in more than one relapse category if several types of relapses were reported at the same follow-up visit. 

^§There are only three grades of paresthesia in version 1 of the Common Toxicity Criteria of the National Cancer Institute.

^†This category included the hand-foot syndrome.

^‡There are only three grades of alopecia in version 1 of the Common Toxicity Criteria of the National Cancer Institute. The incidence of grade 2 alopecia was 5% in each group.

In patients with stage III disease, the relapse hazard ratio (HR) was 0.76 (95% CI 0.62 to 0.92) in the FL+oxaliplatin group compared to the FL group, and the 3-year disease-free survival rate was 72.2% and 65.3%, respectively. In patients with stage II disease, the relapse HR was 0.80 (95% CI 0.56 to 1.15) in the FL+oxaliplatin group compared to the FL group, and the 3-year disease-free survival rate was 87% and 84.3%, respectively. The reduced risk of disease recurrence with FL+oxaliplatin was similar for stage II and III disease (p= 0.77). The reduced risk of relapse was consistent in all subgroups of patients defined on the basis of prognostic factors at baseline. 

Grades 3 and 4 combined reported adverse events were statistically significantly different between treatment regimens except for anemia (p= 0.09), stomatitis (p= 0.41), skin (p= 0.67), and thrombosis or phlebitis (p= 0.29).

Adverse Events

Study Author Conclusions

Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.

InpharmD Researcher Critique

Overall survival of patients was not assessed and survival beyond the cutoff date for data analysis cannot be estimated. In patients taking oxaliplatin who experienced neutropenia, the reversibility rate of the adverse event after holding oxaliplatin doses was not assessed. 

Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07

Design

Phase III, randomized controlled trial 

N= 2,407

Objective

To evaluate the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin (LV) as surgical adjuvant therapy for stage II and III colon cancer

Study Groups

FULV (n= 1,207)

FLOX (n= 1,200)

Inclusion Criteria

Either stage II (T3-4, N0,M0) or stage III (T1-4, N1-2, M0) colon cancer; undergone potentially curative surgical resection with no evidence of residual malignant disease within 42 days before random assignment

Exclusion Criteria

Clinically significant peripheral neuropathy (grade 2 or higher; National Cancer Institute Common Toxicity Criteria Version 2.0), other medical conditions that would preclude chemotherapy administration, history of colon cancer or other invasive cancers

Methods

Eligible patients were randomized to receive either FU 500 mg/m² intravenous (IV) bolus weekly for 6 weeks plus LV 500 mg/m² IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m² IV administered as a 2-hour infusion before LV and FU on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX).

Duration

From February 1, 2000, to November 15, 2002

Outcome Measures

Primary: DFS

Secondary: release-free interval

Baseline Characteristics

FULV (n= 1,207)

FLOX (n= 1,200)

Median age, years

Male

White

Stage

IIA

IIB

IIIA

IIIB

IIIC

TxN1M0

Unknown

27.9%

1.8%

10.7%

34.6%

25.2%

0.5%

0.2% 

26.6%

2.3%

8.8%

36.3%

25.8%

0.1%

0.3%

Location of tumor

Left

Right

Rectosigmoid

Multiple

Unknown

21.1%

40.7%

36.9%

1.2%

0.2%

19.8%

46.2%

33.0%

0.8%

0.3%

Results

Endpoint

FULV (n= 1,207)

FLOX (n= 1,200)

95% confidence interval (CI)

p-Value

DFS

3-year DFS rates

4-year DFS rates

71.8%

67.0%

76.1%

73.2%

0.81 (0.69 to 0.94)*

-

-

0.005* 

-

-

% of patients relapse-free at 4 years

FULV Toxicity Grade, %

Toxicity

Diarrhea

Dehydration

Nausea

Vomiting

Fatigue

NCI-Sanofi Neurosensory

Thrombosis or embolism 

31.6%

11.3%

11.0%

7.7%

3.3%

0.7%

3.8% 

0.6%

0.5%

0.0%

0.7%

0.7%

0.0%

1.1% 

36.9%

16.1

15.6%

12.0%

4.9%

8.2%

3.2%

1.1%

1.1%

0.0%

0.7%

0.4%

0.2%

1.4%

0.003

<0.001

<0.001

<0.001

0.15

<0.001

0.78

*After adjustment for age (≥ 65 vs. < 65) and number of nodes (zero, one to three, or ≥ four)

Adverse Events

See Results

Study Author Conclusions

The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.

InpharmD Researcher Critique

A significant relative risk reduction of 20% in DFS favors the FLOX over the FULV regimen which further confirms and extends the results of the MOSAIC trial. A longer follow-up is warranted to determine the magnitude of survival benefit seen with the regimens including oxaliplatin. 

Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer

Design

Phase IIIb, multicenter, randomized, open-label, parallel-group study.

N= 725

Objective

To evaluate two 5-fluorouracil (5-FU) regimens ± oxaliplatin followed by irinotecan on progression, with the primary objective of demonstrating an improvement in survival on addition of oxaliplatin

Study Groups

Arm A (oxaliplatin plus 5-FU) (n= 362)

Arm B (5-FU) (n= 363)

Inclusion Criteria

Age ≥ 18 years; no prior chemotherapy for metastatic disease; World Health Organisation (WHO) performance status (PS) ≤ 2; no major biochemical/haematologic abnormalities; unidimensionally measurable lesions; completion of any previous adjuvant chemotherapy (not containing oxaliplatin and/or irinotecan) ≥ 6 months before study entry. 

Exclusion Criteria

Resectable disease; unresolved bowel obstruction/diarrhea; peripheral neuropathy (National Cancer Institute Common Toxicity—Criteria Version [NCI-CTC] 2.0 grade ≥ 1); prior malignancies; history of hypersensitivity or intolerance to previous 5-FU; pregnant/lactating females

Methods

Eligible patients with previously untreated metastatic colorectal cancer (mCRC) were randomized to receive either arm A or arm B, each of which was further divided into two subgroups, resulting in four treatment groups (A1, A2, B1, B2). 

Patients in arm A1 received oxaliplatin once every 2 weeks (85 mg/m² 2-hr intravenous [IV] infusion on D1) + 5-FU 250 mg/m²/day continuous intravenous infusion [CIV] given without interruption for the 2-week duration of the treatment cycle (oxaliplatin + 5-FU CIV). Patients in arm A2 had the same oxaliplatin regimen as patients in arm A1 and received 5-FU (400 mg/m² bolus + 600 mg/m² 22-hr CIV on D1, 2) + leucovorin (LV) (200 mg/m² 2-hr IV infusion on D1, 2) (FOLFOX4). Patients in arm B1 received 5-FU 300 mg/m²/day CIV (5-FU CIV) without interruption. Patients in arm B2 received 5-FU (400 mg/m² bolus + 600 mg/m² 22-hr CIV on D1, 2) + LV (200 mg/m² 2-hr IV infusion D1, 2) (LV5FU2). Cycles were repeated every 2 weeks until disease progression or unacceptable toxicity. Irinotecan monotherapy was planned on progression.

Duration

Follow-up: 2 years

Outcome Measures

Primary: survival, defined as the percentage of patients alive at 2 years

Secondary: response rate, progression-free survival (PFS), time-to-treatment failure (TTF), safety

Baseline Characteristics

Arm A (oxaliplatin plus 5-FU) (n= 362)

Arm B (5-FU) (n= 363)

Median age, years (range)

Male

WHO performance status

0

1

2

48%

45%

7%

50%

44%

6%

Haemoglobin, NCI-CTC grade

0/1

≥ 2

94%

6%

93%

7%

Alkaline phosphatase, NCI-CTC grade

0/1

≥ 2

86%

14%

87%

13%

Primary site

Colon

Rectum

Other^a

56%

38%

6%

56%

36%

8%

Number of metastatic sites

0/1

≥ 2

45%

55%

44%

56%

Metastatic sites 

Liver alone

Lung alone

Lymph node disease alone

Other

Liver + other

33%

6%

4%

12%

45%

29%

8%

3%

13%

47%

Prior therapy

Adjuvant chemotherapy

Surgery

27%

87%

26%

86%

Median time since initial diagnosis to metastatic disease, months (range)

^aOther indicates diagnosis of colorectal cancer made by liver or pelvic biopsy (location of primary tumour unknown), synchronous colon and rectal primary tumours and tumours described as ‘colorectal’.

Results

Endpoint

Arm A (oxaliplatin plus 5-FU) (n= 362)

Arm B (5-FU) (n= 363)

Hazard ratio (HR) (95% confidence interval [CI])

p-Value

2-year survival rate

27.3%

24.8%

0.93 (0.78–1.10)

Median overall survival, months

15.9

15.2

-

Overall response rate (complete response [CR] + partial response [PR])

54.1%

29.8%

-

Response category

CR

PR

Stable response

Progressive disease

Not evaluable

Not done/missing data

24 (6.6%)

172 (47.5%)

76 (21.0%)

46 (12.7%)

8 (2.2%)

36 (9.9%)

6 (1.7%)

102 (28.1%)

128 (35.3%)

89 (24.5%)

4 (1.1%)

34 (9.4%)

Median PFS, months

Median TTF, months

Adverse Events

Common Adverse Events: grade 3/4 neutropenia (arm A, 33%; arm B, 5%), grade 3/4 diarrhea (arm A, 14%; arm B, 8%), and grade 3/4 fatigue (arm A, 9%; arm B, 8%).

Serious Adverse Events: arm A, 424 events; arm B, 310 events

Percentage that Discontinued due to Adverse Events: arm A, 17%; arm B, 5%

Study Author Conclusions

Despite improved rates of tumor control, these results failed to demonstrate a survival benefit from the addition of oxaliplatin to infused 5-FU and lend further support to the use of sequential monotherapy in some patients with mCRC.

InpharmD Researcher Critique

This study did not meet its primary efficacy endpoint of survival benefits. Statistically significant overall response rates and PFS were merely secondary endpoints. A cross-over design may have optimized the ability to evaluate the true impact of adding oxaliplatin to 5-FU and LV in mCRC.

Comparison of efficacy results with previous studies of oxaliplatin plus 5-FU ± LV versus 5-FU ± LV alone 

Cunningham et al., 2009

Oxaliplatin + CIV 5-FU/ FOLFOX4

CIV 5-FU/LV5FU2

362 (58/304)

363 (62/301)

27%

26%

54%

61%

54.1****

29.8

7.9**** (9.0/7.9)

5.9 (6.4/5.9)

15.9 (19.6/15.5)

15.2 (16.7/14.8)

Seymour et al., 2007¹

5-FU/LV

5-FU/LV/OX^a

1,393

344

24%

26%

52%

52%

28***

57

6.3***

8.7

NR

15.4

Hospers et al., 2006²

5-FU/LV/OX^b

5-FU/LV

151

151

14%

12%

60%

64%

33.8**

18.5

6.7*

5.6

13.8

13.3

Grothey et al., 2002³

FULFOX^c

Mayo 5-FU/LV bolus

118

124

15

25

75

75

48.3****

22.6

7.9****

5.3

20.4

16.1

de Gramont et al., 2000⁴

FOLFOX4

LV5FU2

210

210

20%

20%

58%

60%

50.7****

22.3

9.0***

6.2

16.2

14.7

Giacchetti et al., 2000⁵

Oxaliplatin + chrono 5-FU/LV^d

Chrono 5-FU/LV

100

100

10%*

23%

NR

57%

53***

16

8.7*

6.1

19.9

19.4

^aOxaliplatin 85 mg/m2 plus levofolinate 175 mg concurrent over 2h, then 5-FU 400 mg/m2 (bolus) and 2,600 mg/m2 over 46h, every 2 weeks.

^bOxaliplatin 85 mg/m² over 2h, LV 200 mg/m² over 1h, 5-FU 2,600 mg/m² over 24h, on day 1 every 2 weeks.

^c5-FU 2,000 mg/m² over 24h, LV 500 mg/m² over 2h, oxaliplatin 50 mg/m² over 2h, weekly for 4 of 5 weeks, then every 2 weeks.

^dOxaliplatin 125 mg/m² over 6h, 5-FU 700 mg/m², LV 300 mg/m² (peak delivery rate at 0400 h), every 3 weeks.

****p≤ 0.0001; ***p≤ 0.001; **p≤ 0.01; *p< 0.05 versus controls.

Chrono, chronomodulated; CIV, continuous intravenous infusion; 5-FU, 5-fluorouracil; LV, leucovorin; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TTP, time to progression.

Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer

Design

Randomized, comparative trial

N= 420

Objective

To investigate the effect of combining oxaliplatin with leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks (LV5FU2) on progression-free survival

Study Groups

LV5FU2 (n= 210)

LV5FU2 + oxaliplatin [FOLFOX4] (n= 210)

Inclusion Criteria

Adenocarcinoma of the colon or rectum; unresectable metastases; at least one bidimensionally measurable lesion of ≥ 2 cm; adequate bone marrow, liver, and renal function; World Health Organization (WHO) performance status of 0 to 2; age 18 to 75 years; ability to complete quality of life (QoL) questionnaires; previous adjuvant chemotherapy, if given, must have been completed ≥ 6 months before inclusion

Exclusion Criteria

Patients with CNS metastases, second malignancies, or disease confined to previous radiation fields

Methods

All eligible patients received a 2-hour infusion of LV (200 mg/m²/d) followed by a 5FU bolus (400 mg/m²/d) and 22-hour infusion (600 mg/m²/d) for 2 consecutive days every 2 weeks. In addition, patients were randomized to also receive either oxaliplatin 85 mg/m² in 250 mL of dextrose 5% as a 2-hour infusion concurrently with LV on day 1 (FOLFOX4) or no additional treatment (LV5FU2). Patients on the FOLFOX4 regimen also received antiemetic prophylaxis with a 5-hydroxytryptamine-3–receptor antagonist but antiemesis was not necessary for patients on the LV5FU2 regimen. Treatment was discontinued when the disease progressed, unacceptable toxicity occurred, or by patient choice. FOLFOX4 students received a median of 12 treatment cycles while LV5FU2 patients received a median of 11 treatment cycles. Outpatient administration of the chemotherapy regimens was completed with implantable ports and disposable or electronic pumps. 

The 5FU dose was reduced after a National Cancer Institute common toxicity criteria grade ≥ 3 diarrhea, stomatitis, or dermatitis occurred. Oxaliplatin was reduced for grade 3/4 neutropenia, and in cases of persistent (≥ 14 days) paresthesia or temporary (7 to 14 days) painful paresthesia or functional impairment. In cases of persistent (≥ 14 days) painful paresthesia or functional impairment, oxaliplatin was discontinued from the regimen until recovery.

Duration

August 1995 to July 1997

Outcome Measures

Treatment response parameters, prognostic factors, quality of life, and adverse events

Baseline Characteristics

LV5FU2 (n= 210)

FOLFOX4 (n= 210)

Median age, years

Female

WHO performance status

0

1

2

48.6%

41.9%

9.5%

43.3%

46.2%

10.5%

Primary site

Colon

Rectum

Multiple or not specified

70%

29%

1% 

71.9%

28.1%

0 

Metastatic site

Liver

Lung

Other

82.4%

30%

11.4%

86.7%

23.4%

12.4%

No. of sites

1

≥2

40%

60%

42.9%

57.1% 

Carcinoembryonic antigen

Normal

1-20x normal

>20x normal

17.6%

43.8%

34.8% 

14.8%

45.2%

36.2%

Laboratory values

Increased alkaline phosphatase

Increased lactate dehydrogenase

45.2%

44.8%

50.5%

46.2% 

Adjuvant chemotherapy

Yes

No

20.5%

79.5% 

20%

80% 

5-FU dose intensity

First 4 cycles

All cycles

92%

69%

84%

86%

Results

Endpoint

LV5FU2 (n= 210)

FOLFOX4 (n= 210)

p-Value

Overall

Overall response rates (95% confidence interval)

Complete response (CR), n

Partial response (PR), n

Stable disease, n

Disease progression, n

Median time to response, weeks

Median duration of response, weeks

21.9% (17.9 to 25.9%)

1 (0.5%)

45 (21.4%)

107 (51%)

34 (16.2%) 

12

46.1

50% (46.1% to 54.9%)

3 (1.4%)

102 (48.6%)

67 (31.9%)

21 (10%)

9

45.1

0.0001

--

--

--

-- 

--

--

Response (CR/PR) by age

≤ 65 years

> 65 years

28 (22.2%)

18 (21.4%)

67 (50%)

38 (50%)

--

--

Response (CR/PR) by disease

Synchronous

Metachronous

Liver only

Liver + other sites

Other sites

32 (23%)

14 (20%)

16 (23.6%)

23 (21.9%)

7 (18.9%)

76 (56.3%)

29 (41.4%)

43 (54.4%)

54 (52.4%)

8 (28.6%)

--

--

--

--

-- 

Response (CR/PR) by prior adjuvant chemotherapy

Yes

No

6 (14%)

40 (23.9%) 

16 (38.1%)

89 (53%)

--

--

Median survival, months

Progression-free

Overall

6.2

14.7 

9.0

16.2 

0.0001

0.12

Adverse Events significantly different between groups

Neutropenia

Grade 3

Grade 4

Nausea

Grade 3

Grade 4

Vomiting

Grade 3

Grade 4

Diarrhea

Grade 3

Grade 4

Mucositis

Grade 3

Grade 4

Neurologic toxicity

Grade 3

Grade 4

3.8%

1.5%

2.0%

N/A

1.5%

0.5%

3.8%

1.5%

1.5%

0

0

N/A

29.7%

12.0%

5.7%

N/A

4.3%

1.5%

8.6%

3.3%

5.3%

0.5%

18.2%

N/A

<0.001

0.043

0.043

0.015

0.019

<0.001

Two independent prognostic factors were found to be significant for treatment response in the multivariate analysis: treatment allocation to oxaliplatin and synchronous metastases. Three independent prognostic factors were significant for improved progression-free survival: treatment allocation to oxaliplatin, low lactate dehydrogenase level, and good performance status. Independent prognostic factors significant for improved overall survival were treatment allocation to oxaliplatin, low lactate dehydrogenase level, good performance status, low alkaline phosphatase level, and a limited number of involved sites. 

Median overall quality of life scores were comparable for both treatment arms, however, the time to deterioration of the global health status of 20% or 40% was significantly prolonged in the FOLFOX4 arm (p= 0.0039 and p= 0.0004, respectively).

Although grade 3/4 neutropenia was common in the FOLFOX4 arm, patients responded well to dose modification and few complications were seen. Only 22 patients (10.5%) had more than one episode, and only two patients (1%) experienced febrile neutropenia.

Adverse Events

Study Author Conclusions

The LV5FU2+oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.

InpharmD Researcher Critique

Since patients could discontinue treatment by choice and patients not experiencing favorable effects are more likely to discontinue treatment, this could skew results into appearing more favorable. Dose reductions due to adverse effects may have had an impact on patient outcomes and subsequently study results. 

Comparative effectiveness of 5-fluorouracil with and without oxaliplatin in the treatment of colorectal cancer in clinical practice

Design

Retrospective cohort study

N= 636

Objective

To examine whether patterns of overall survival (OS) associated with oxaliplatin versus non-oxaliplatin containing intravenous (IV) and oral 5-fluorouracil (5-FU) treatment of colorectal cancer (CRC) in practice are consistent with those observed in randomized controlled trials (RCTs)

Study Groups

Capecitabine (oral form of 5-FU) (n= 187)

XELOX (capecitabine/oxaliplatin) (n= 43)

FOLFOX (5-FU/leucovorin [LV]/oxaliplatin) (n= 339)

5-FU/LV (n= 67)

Inclusion Criteria

Patients diagnosed with CRC based on South Eastern Sydney and Illawarra Area Health Service (SESIAHS) Clinical Cancer Registry (ClinCR) who were treated with different variations in 5-FU treatment during the data collection period

Exclusion Criteria

Patients who underwent chemotherapy more than once, or changed chemotherapy (excluded in comparative survival analyses)

Methods

Practice variation in 5-FU treatment of patients with CRC was analyzed between modalities by patient age, tumor stage, and site using non-parametric tests. Comparative survival analyses (n=434) were conducted over a three-year follow-up period using Cox regression, adjusting for observed confounders.

Duration

Data collection: between 1 January, 2006 and 31 December, 2009

Follow-up: 3 years

Outcome Measures

OS rates

Baseline Characteristics

Capecitabine (n= 187)

XELOX (n= 43)

FOLFOX (n= 339)

Age at diagnosis, years

Degree of spread/TNM¹ stage

Localized to tissue of origin/I (n= 17)

Invasion of adjacent tissues/organs /II (n= 60)

Regional lymph nodes/III (n= 329)

Distant metastasis/IV (n= 228)

Unknown² (n= 2)

1.1%

4.9%

13.7%

9.4%

0.3%

0%

0.2%

2.7%

3.9%

0%

0.8%

1.6%

28.9%

22.0%

0%

0.8%

2.8%

6.4%

0.5%

0% 

Tumor site

Colon (n= 441)

Rectum (n= 195)

17.9%

11.5%

5.5%

1.3%

41.5%

11.8%

4.4%

6.1%

¹TNM classification of malignant tumours based on tumour size, lymph node involvement and metastasis

²Excluded from statistical analysis

Change in chemotherapy treatment or receipt of second round of treatment (n= 107) occurred more frequently with individuals whose first treatment was either XELOX (30.2%) or FOLFOX (19.8%). The reasons for changing therapy are not reported but are expected to be due to relapse and toxicity.

Results

Cox regression analysis for survival outcomes: 5-FU treatment effect (excludes patients treated with more than one round of chemotherapy)¹

Hazard ratio (HR)² (95% confidence interval [CI])

p-Value

Evidence of non-proportionality

5-FU/LV (ref) vs. FOLFOX

Capecitabine (ref) vs. XELOX

IV 5-FU (ref) vs. oral 5-FU

¹Adjusted for colon/rectal, sex, age, stage of cancer, and whether the patient also had surgery or radiotherapy.

²Values >1 favor the reference (ref) treatment.

Adverse Events

Not disclosed

Study Author Conclusions

Our findings suggested no survival benefit with the addition of oxaliplatin to 5-FU modalities in treating CRC in practice. This raises questions as to the net benefit of oxaliplatin, given its known toxicity profile and expense.

InpharmD Researcher Critique

The study is subject to the limitations inherent to a retrospective analysis consisting of only an Australian cohort. The Cox regression analyses found no significant difference in survival with the addition of oxaliplatin to 5-FU regimens. The study further lacked detailed comorbidity information to allow for the expected impacts of comorbidity factors on selected chemotherapy in CRC.