Capecitabine, tablet, 150 mg and 500 mg, Xeloda® - March 2011
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Public Summary Document
Product: Capecitabine, tablet, 150 mg and 500 mg,
Xeloda®
Sponsor: Roche Products Pty Limited
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought the PBS listing of capecitabine to include
use in combination with oxaliplatin for the adjuvant treatment of
stage III (Dukes C) colon cancer.
2. Background
Capecitabine has been listed on the PBS since 1 November
1999.
In November 2005, the PBAC recommended extending the listing for
capecitabine to include the adjuvant treatment of patients with
Dukes C colon cancer on a cost-minimisation basis with the Mayo
Clinic regimen for 5-FU plus leucovorin. Listing was effective from
1 April 2006.
Oxaliplatin had not previously been considered by the PBAC for the
adjuvant treatment of colorectal cancer in combination with
capecitabine but is currently listed for the adjuvant treatment of
stage III colorectal cancer in combination with 5-fluorouracil and
folinic acid. Listing was effective 1 December 2005.
3. Registration Status
Oxaliplatin
As at 2 February 2011, oxaliplatin TGA registered indications were extended to include:
- adjuvant treatment of stage III (Duke's C) colon cancer, in combination with a fluoropyrimidine agent.
Capecitabine
As at 2 February 2011, capecitabine TGA registered indications were
amended as follows:
Colon Cancer
- the adjuvant treatment of patients with Dukes stage C and high-risk stage B colon cancer, either as monotherapy or in combination with oxaliplatin.
4. Listing Requested and PBAC’s View
CAPECITABINE
No amendments to the current listing:
Authority required
Adjuvant treatment of stage III (Dukes C) colon cancer, following
complete resection of the primary tumour.
NOTE
:In the adjuvant setting, the recommended treatment duration is 24
weeks.
Alternatively, it was proposed that the following PBS
restriction be amended as follows highlighted by
italics:
Authority required
Adjuvant treatment of stage III (Dukes C) colon cancer, either
as monotherapy or in combination with oxaliplatin, following
complete resection of the primary tumour.
NOTE:
In the adjuvant setting, the recommended treatment duration is 24
weeks.
OXALIPLATIN
Authority required
Adjuvant treatment of stage III (Dukes C) colon cancer, in
combination with a fluoropyrimidine agent.
NOTE: In the adjuvant setting, the recommended treatment
duration is 24 weeks.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Colorectal cancer accounts for approximately 14% of all cancer
registrations and is the second most common cancer in
Australia.
Adjuvant chemotherapy has become the standard of care for stage III
colon cancer patients (includes tumours with metastases in regional
lymph nodes but no distant metastases) as it can reduce the
likelihood of recurrence and improve overall survival in these
patients.
The submission proposed that the place in therapy of combination
oral capecitabine and intravenous oxaliplatin is as an alternative
to intravenous combination chemotherapy regimens containing
oxaliplatin, 5-fluorouracil and folinic acid in patients with good
performance status who are able to tolerate oxaliplatin-based
chemotherapy for the adjuvant treatment of colon cancer.
6. Comparator
The submission nominated oxaliplatin with 5-fluorouracil and
leucovorin (described as FOLFOX and FLOX regimens) as the main
comparator, which was considered appropriate by the PBAC.
7. Clinical Trials
The basis of the submission was an indirect comparison of XELOX vs.
FOLFOX/FLOX for the adjuvant treatment of colon cancer using
5-FU/LV as the common comparator.
The submission included one trial of XELOX vs. 5-FU/LV (NO16968),
one trial of FOLFOX-4 vs. 5-FU/LV (MOSAIC) and one trial of FLOX
vs. 5-FU/LV (NSABP C-07).
The trials published at the time of submission are presented in the
following table:
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
| XELOX vs. 5-FU/LV | ||
| NO16968 | ||
| Schmoll HJ et al | Phase III trial of capecitabine plus oxaliplatin as adjuvant treatment for Stage III colon cancer: a planned safety analysis in 1,864 patients. | Journal of Clinical Oncology, 2007, 25(1): 102-109 |
| Schmoll HJ et al | Final safety findings from a randomised phase III trial of capecitabine + oxaliplatin (XELOX) vs bolus 5-FU/LV as adjuvant therapy for patients (I) with Stage III colon cancer. | Journal of Clinical Oncology, ASCO Annual Meeting Proceedings (Post-Meeting Edition), 2006, 24(18S): June 20 Supplement: 3569 |
| FOLFOX vs. 5-FU/LV | ||
| MOSAIC | ||
| Andre T et al | Improved overall survival with oxaliplatin, fluorouracil and leucovorin as adjuvant treatment in Stage II or III colon cancer in the MOSAIC trial. | Journal of Clinical Oncology, 2009, 27(19): 3109-3116 |
| Andre T et al | Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. | New England Journal of Medicine, 2004, 350(23): 2343-2351 |
| De Gramont A et al | Oxaliplatin/5FU/LV in the adjuvant treatment of Stage II and Stage III colon cancer: efficacy results with a median follow-up of 4 years. | Journal of Clinical Oncology, ASCO Annual Meeting Proceedings, 2005, 23(16S): 3501 |
| ASCO lectures. Available on website. Accessed May 24 2010 | ||
| FLOX vs. 5-FU/LV | ||
| NSABP C-07 Kuebler JP et al | Severe enteropathy among patients with stage II/III colon cancer treated on a randomised trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin. | Cancer, 2007, 110(9): 1945-1950 |
| Kuebler JP et al | Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. | Journal of Clinical Oncology, 2007, 25(16): 2198-2204 |
| Land SR | A brief review of results from NSABP protocol C-07: Neurotoxicity with oxaliplatin combined with 5-fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer. | American Journal of Hematology/Oncology, 2007, 6(11): 634-637 |
| Land SR et al | Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for Stage II and III colon cancer: NSABP C-07. | Journal of Clinical Oncology, 2007, 25(16): 2202-2211 |
| Land SR et al | Patient-reported neurotoxicity with FULV versus FLOX in patients with Stage II or III carcinoma of the colon: Results of NSABP protocol C-07. | Journal of Clinical Oncology, ASCO Annual Meeting Proceedings, 2006, 24(18S): 3564 |
| Yothers G et al | Neurotoxicity (NT) in colon cancer (CC) survivors from NSABP protocol C-07 comparing 5-FU + leucovorin (FULV) with the same regimen + oxaliplatin (FLOX): Preliminary results from NSABP protocol LTS-01 | Journal of Clinical Oncology, ASCO Annual Meeting Proceedings, 2008, 26(15S): 9575 |
| Wolmark N et al | A phase III trial comparing FULV to FULV + oxaliplatin in Stage II or III carcinoma of the colon: Survival results of NSABP protocol C-07 | Journal of Clinical Oncology, ASCO Annual Meeting Proceedings, 2008, 26: LBA4005 |
The 5-FU/LV treatment arm was the common comparator used in each of
the included studies. However, the dose regimen used in the 5-FU/LV
treatment arms varied between trials. The submission claimed that
all dosing regimens of 5-FU/LV had been shown to have comparable
efficacy in the adjuvant setting (based on published studies by
Andre et al 2003, Andre et al 2005; Carrato et al 2006; Chau et al
2005; Poplin et al 2005; Saini et al 2003 and Wils et al 2001). The
PBAC considered this claim was reasonable, see Recommendation
and Reasons.
8. Results of Trials
The primary outcome of all trials was disease-free survival at 3
years which was the primary outcome used in the submission.
The survival measures used in the trials were defined as follows:
- Disease-free survival: Time from randomisation to the time of the first event (recurrence of the original colon cancer, development of a new colon or rectal cancer, or death due to any cause)
- Overall survival: Time from randomisation to death from any cause
- Relapse-free survival: Time from randomisation to the time of the first event (recurrence of the original colon cancer, development of a new colon or rectal cancer or deaths due to treatment, tumour recurrence or new colorectal cancer)
Results of the indirect comparison – 3-year disease-free survival
All oxaliplatin chemotherapy regimens (XELOX, FOLFOX-4 and FLOX)
improved disease-free survival compared to 5-FU/LV alone. The
relative treatment benefit of oxaliplatin regimens appeared to be
maintained over time. The improvement in disease-free survival was
only statistically significant in the overall/Stage III patient
populations. No treatment had demonstrated a statistically
significant benefit in Stage II disease.
The indirect analysis did not identify any statistically
significant difference in disease-free survival with XELOX vs.
FOLFOX-4 (HR 1.05; 95% CI 0.82, 1.35) or with XELOX vs. FOLFOX/FLOX
(HR 1.01; 95% CI 0.84, 1.22). Based on the data presented in the
submission it appeared that disease-free survival is comparable
between the various oxaliplatin treatment regimens.
Results of the indirect comparison – 3-year overall survival
FOLFOX-4 is the only oxaliplatin regimen that has demonstrated a
statistically significant improvement in overall survival compared
to 5-FU/LV. However, statistical significance was only reached
after 6 years of patient follow-up. Subgroup analyses of the MOSAIC
trial suggest that the overall survival improvement associated with
FOLFOX-4 treatment is limited to Stage III patients only.
Although not statistically significant, the overall survival
results favour XELOX compared to 5-FU/LV.
The indirect analysis did not identify any statistically
significant difference in overall survival with XELOX vs. FOLFOX-4
(HR 1.01; 95% CI 0.73, 1.39). Overall survival appeared to be
comparable between treatments. However, at 3 years (the only time
point available for the indirect analysis), neither treatment had
demonstrated a statistically significant difference in overall
survival compared to 5-FU/LV.
Results of the indirect comparison – recurrence-free survival
Both XELOX and FLOX demonstrated a statistically significant
improvement in recurrence-free survival compared to 5-FU/LV.
The indirect analysis did not identify any statistically
significant difference in recurrence-free survival with XELOX vs.
FLOX (HR 0.98; 95% CI 0.77, 1.23). Despite the limitations of this
analysis (different patient populations and follow-up times between
trials), the results of the indirect comparison suggested that
recurrence-free survival is comparable between treatments.
All oxaliplatin regimens (XELOX, FOLFOX-4 and FLOX) appeared to be
more toxic than 5-FU/LV treatment and there were differences in the
toxicity profiles of the various oxaliplatin regimens.
Based on an indirect analysis of adverse events, XELOX is
associated with a lower incidence of diarrhoea, nausea/vomiting,
stomatitis, neutropenia and febrile neutropenia compared to
FOLFOX-4 but is associated with an increased risk of hand-foot
syndrome.
9. Clinical Claim
The submission described XELOX as no worse than FOLFOX/FLOX in
terms of comparative effectiveness and safety in the treatment of
patients with Stage III adjuvant colon cancer, which the PBAC
considered reasonable.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost analysis model of XELOX vs.
mFOLFOX-6 with the intention to demonstrate cost-minimisation. The
submission claimed that mFOLFOX-6 is the appropriate economic
comparator as it is the most commonly used chemotherapy regimen for
the adjuvant treatment of colon cancer in Australia.
XELOX was associated with a cost saving per patient compared to
mFOLFOX-6 based on the cost analysis model presented in the
submission.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients/year to be
less than 10,000 in Year 5.
The submission estimated the financial cost/year to the PBS to be
less than $10 million in Year 5 with overall annual cost savings to
the health care budget, both State and Commonwealth, over the first
five years of listing.
12. Recommendation and Reasons
The PBAC recommended the listing of capecitabine in combination with oxaliplatin (XELOX)
on the PBS for the adjuvant treatment of stage III (Dukes C) colon cancer on a cost-minimisation
basis compared with modified FOLFOX-6. The PBAC considered that the equi-effective
doses are XELOX (capecitabine 1000 mg/m2 twice daily days 1-14 and oxaliplatin 130 mg/m2 day 1 given every 21 days) and m-FOLFOX-6.
The PBAC recommended that the restriction for capecitabine be amended to include “monotherapy
or in combination with oxaliplatin for the adjuvant treatment of colon cancer”, consistent
with the ACPM recommended wording and that the restriction for oxaliplatin be amended
to include “in combination with capecitabine or 5-fluorouracil and folinic acid” rather
than “in combination with a fluoropyrimidine agent” to reflect more appropriately
the drug combinations used in the clinical trials.
The PBAC considered that the main comparator, oxaliplatin with 5-fluorouracil and
folinic acid (described as FOLFOX and FLOX regimens) was appropriate.
The PBAC noted that the submission presented an indirect comparison of XELOX, FOLFOX-4
and FLOX. However, the included trials enrolled different patient populations (Stage
II/Stage III disease) and used different 5-FU/LV (leucovorin (folinic acid)) treatment
regimens in the common comparator arm. The PBAC considered that the submission had
adequately addressed these differences.
The PBAC considered the clinical claim in the submission that XELOX is no worse than
FOLFOX/FLOX in terms of comparative effectiveness and safety in the treatment of patients
with Stage III adjuvant colon cancer was reasonable as the indirect analysis suggests
that disease-free, recurrence-free and overall survival are similar between oxaliplatin
regimens (XELOX, FOLFOX-4 and FLOX). The PBAC agreed that whilst the statistical evidence
does not, on its own, demonstrate non-inferiority, the conversion of capecitabine
to 5FU and the point estimates of the hazard ratios being close to 1 suggests non-inferiority.
The PBAC noted that a breakdown of drug administration costs (conducted during the
evaluation) showed that the difference in drug administration costs is primarily driven
by the cost of removing the 5-FU delivery device in the mFOLFOX-6 treatment arm. The
PBAC noted that the sensitivity analysis presented in the Pre-Sub-Committee Response
removed the disconnection cost of the 5-FU device for mFOLFOX-6 but that this still
resulted in a cost saving per patient.
The PBAC also acknowledged the option of an oral treatment for patients in this treatment
setting was valuable.
Recommendation:
CAPECITABINE, tablet, 150 mg and 500 mg
Amend the current restriction for use in adjuvant treatment of stage III (Dukes C)
colon cancer to read as follows:
Authority required
Adjuvant treatment of stage III (Dukes C) colon cancer following complete resection of the primary tumour either as
(a)monotherapy; or
(b) in combination with oxaliplatin,
NOTE:
In the adjuvant setting, the recommended treatment duration is 24 weeks.
Capecitabine is not PBS-subsidised for the treatment of patients with stage II (Dukes B) colon cancer.
Capecitabine is not PBS-subsidised for the adjuvant treatment of patients with rectal cancer.
Max qty: 120 (500 mg), 60 (150 mg)
Repeats: 2
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor had no further comment.
