Raadpleeg ook literatuurlijst niet-toxische stoffen en behandelingen specifiek bij darmkanker  van arts-bioloog drs. Engelbert Valstar

7 oktober 2019: zie ook dit artikel: 

https://kanker-actueel.nl/NL/mfolfox6-fluorouracil-leucovorin-en-oxaliplatin-met-of-zonder-radiotherapie-vooraf-aan-operatie-geeft-geen-betere-overall-overleving-voor-gevorderde-endeldarmkanker-dan-alleen-fluorouracil-5-fu-plus-radiotherapie.html

1 september 2019: Bron: European Journal of Cancer

Uit een fase II studie blijkt dat, wanneer een behandeling op basis van oxaliplatin (FOLFOX = fluorouracil, leucovorin, en oxaliplatin) samen met panitumumab eerst wordt gebruikt bij uitgezaaide darmkanker, het beter is om met oxaliplatin te stoppen en na zes tot acht cycli chemokuren (3-4 maanden) een onderhoudsbehandeling te volgen. Deze benadering geeft namelijk geen verschil in het resultaat op progressievrije ziekte en overall overleving, maar vermindert wel de opbouwende neurotoxiciteit.

Belangrijkste bevindingen van deze studie:

  • Het stoppen van oxaliplatin na zes cycli van chemokuur fluorouracil, leucovorin en oxaliplatin (mFOLFOX6) plus panitumumab is een mogelijke behandelingsoptie. 
  • De werkzaamheid na het stoppen van oxaliplatin is vergelijkbaar met mFOLFOX6 plus panitumumab.
  • Stoppen met oxaliplatin vermindert neuropathie versus mFOLFOX6 plus panitumumab.

Er werden geen duidelijke verschillen waargenomen tussen de studie groepen. In totaal hadden 55 patiënten in groep A en 53 in groep B de RAS-ziekte (KRAS / NRAS positief). Zie Table 1.

De resultaten op progressievrije ziekte waren nagenoeg gelijk tussen beide groepen:

Table 2Summary of PFS rates and RRs (FAS).
PFS and tumour responseGroup A (n = 56)Group B (n = 57)
PFS rate, % (80% CI) 46.4 (38.1–54.9) 47.4 (39.1–55.8)
H0: PFS rate ≤30% p = 0.0037 p = 0.0021
Best response, n (%)
 CR 8 (14.3) 2 (3.5)
 PR 37 (66.1) 48 (84.2)
 SD 4 (7.1) 3 (5.3)
 PD 6 (10.7) 4 (7.0)
 NE 1 (1.8) 0 (0.0)
RR, % (95% CI) 80.4 (68.0–88.8) 87.7 (76.4–94.2)
View Table in HTML

CI, confidence interval; CR, complete response; FAS, full analysis set; H0, null hypothesis; NE, not evaluable; PD, progressive disease; PFS, progression-free survival; PR, partial response; RR, response rate; SD, stable disease.

Fig. 2 Opens large image

Fig. 2

Kaplan–Meier plots of (A) PFS, (B) TTF and (C) OS in patients receiving mFOLFOX6 plus panitumumab or 5-FU/LV plus panitumumab after six cycles of front-line mFOLFOX6 plus panitumumab therapy (day 0: time of randomisation; FAS). 5-FU, fluorouracil; CI, confidence interval; FAS, full analysis set; HR, hazard ratio; LV, leucovorin; mFOLFOX6, modified FOLFOX (fluorouracil, leucovorin and oxaliplatin); OS, overall survival; PFS, progression-free survival; TTF, time to treatment failure.

Hier het abstract van de studie:

SAPPHIRE: a randomised phase II study of planned discontinuation or continuous treatment of oxaliplatin after six cycles of modified FOLFOX6 plus panitumumab in patients with colorectal cancer

Y. Munemotoa
M. Nakamurab
M. Takahashic
M. Kotakad
H. Kurodae
T. Katof,g
N. Minagawah
S. Nourai
M. Fukunagaj
H. Kuramochik
T. Touyamal
T. Takahashim
K. Miwan
H. Satakeo,p
S. Kurosawaq
T. Miuraq
H. Mishimar
J. Sakamotos
K. Obat
N. Nagatae,∗,'Correspondence information about the author N. Nagata
Open Access

Highlights

  • Stopping oxaliplatin after six cycles of modified fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) plus panitumumab is a potential treatment option.

  • Efficacy after stopping oxaliplatin is similar to mFOLFOX6 plus panitumumab.

  • Stopping oxaliplatin reduces peripheral neuropathy vs mFOLFOX6 plus panitumumab.

Abstract

Background

Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence.

Patients and methods

Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety.

Results

In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval , 38.1–54.9) and 9.1 months (95% CI, 8.6–11.1) in group A, compared with 47.4% (80% CI, 39.1–55.8) and 9.3 months (95% CI, 6.0–13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%).

Conclusion

Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab.

4. Discussion

SAPPHIRE is the first randomised trial to evaluate the planned discontinuation of oxaliplatin treatment after mFOLFOX plus anti-EGFR antibody. The results of this study indicate that the planned discontinuation of oxaliplatin treatment reduced PN without any reduction in efficacy.

Several studies have evaluated cetuximab or panitumumab as monotherapy or combined with 5-FU/LV as maintenance therapy after oxaliplatin-based chemotherapy plus anti-EGFR antibody as induction therapy. The MACRO-2 study showed that cetuximab monotherapy as maintenance after induction with eight cycles of mFOLFOX6 plus cetuximab resulted in similar efficacy, yet reduced incidence of neuropathy compared with continued mFOLFOX6 plus cetuximab [15]. However, the VALENTINO study, comparing panitumumab monotherapy or 5-FU/LV plus panitumumab after eight cycles of induction therapy with FOLFOX plus panitumumab, showed that monotherapy was inferior in terms of 10-month PFS rates [16]. Similarly, a recent retrospective analysis of the PEAK and PRIME studies showed that maintenance with panitumumab plus 5-FU/LV after 11–12 cycles of an oxaliplatin-containing regimen was well tolerated and may be associated with better outcomes than strategies not containing panitumumab [17]. Thus, anti-EGFR antibody monotherapy may not be a suitable treatment option after oxaliplatin-based induction chemotherapy regarding efficacy. Our results suggest that maintenance therapy with 5-FU/LV plus panitumumab could be a more useful option regarding efficacy and safety than continued oxaliplatin treatment after six cycles of FOLFOX plus panitumumab, despite a relatively shorter induction duration and lower cumulative oxaliplatin dose than previous studies. The median duration of oxaliplatin treatment in the present study was 6.8 months, including the 3-month induction period, and the median cumulative dose of oxaliplatin was 813 mg/m2 in group A, which was similar to other studies [115].

In patients receiving chemotherapy plus an EGFR antibody, those with left-sided tumours are reported to have superior OS, PFS and RR than those with right-sided tumours [1819]. Although a limited number of patients were evaluated in our study, patients with left-sided tumours also had superior PFS and RR. In addition, subgroup analysis in our study suggested that the planned discontinuation of oxaliplatin did not affect efficacy in patients with left- or right-sided tumours.

There are several limitations in the present study that warrant mention. First, the present study was designed to be a non-definitive screening comparison of an experimental treatment regimen against a randomised standard-treatment control arm [20]. It was not designed to show non-inferiority of group B to group A as the primary end-point. For primary end-point analysis, the threshold PFS rate at 9 months for futility of 30% was based on a phase II single-stage design [421]. However, both groups A and B exceeded the 30% threshold and exploratory statistical analysis suggested a similar level of efficacy in both groups A and B, as shown in the equivalent HR for PFS. We therefore consider 5-FU/LV plus panitumumab to be a promising regimen. Second, the follow-up period was not long, and the OS data were immature. In addition, patients with BRAF mutations were not examined in this study. However, as the population of patients with mCRC and BRAF mutations in Japan has been reported as 5.4% [22], the proportion of these patients was also low in the present study. Given that the present study was randomised, we consider the impact of patients with mCRC and BRAF mutations on the outcome of each group to be equivalent.

In conclusion, the SAPPHIRE study showed that the planned discontinuation of oxaliplatin treatment after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC. Further investigation should help validate the non-inferiority of oxaliplatin discontinuation after mFOLFOX6 plus anti-EGFR antibody as induction therapy for patients with mCRC. A phase II study of maintenance therapy with 5-FU/LV plus panitumumab versus 5-FU/LV alone after FOLFOX plus panitumumab in patients with mCRC (PanaMa; NCT01991873) is underway, which will help inform the results of the present study.

Trial registration number

NCT02337946


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