GAMEC--a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours

Abstract

There is no consensus as to the management of untreated poor prognosis or relapsed/refractory germ cell tumours. We have studied an intensive cisplatin-based regimen that incorporates high-dose methotrexate (HD MTX) and actinomycin-D and etoposide every 14 days (GAMEC). Sixty-two patients were enrolled in a phase 2 study including 27 who were untreated (IGCCCG, poor prognosis) and 35 with progression despite conventional platinum based chemotherapy. The pharmacokinetics of the drugs were correlated with standard outcome measures. Twenty of the untreated patients were progression free following GAMEC and appropriate surgery, as were 18 individuals in the pretreated group. None of the established prognostic factors for therapy for pretreated patients could identify a poor-prognosis group. Five out of nine late relapses to prior chemotherapy were progression free following GAMEC and appropriate surgery. All patients had at least one episode of febrile neutropenia and there were five (8%) treatment-related deaths. PK values were not predictive of efficacy or toxicity, although the dose intensity in the pretreated group of patients, especially of HD MTX, was significantly correlated with progression-free survival (PFS). GAMEC is a novel intensive regimen for this group of patients producing encouraging responses, although with significant toxicity. For those in whom it fails, further therapy is still possible with durable responses being seen.

Figure 1

GAMEC chemotherapy schedule. Week 1: actinomycin-D (1 mg m⁻²) day 1: etoposide: 90 mg m⁻², days 1–4 over 2 h; MTX loading dose over 30 min followed by 12 h infusion; day starting 4 h after the etoposide: cisplatin 50 mg m⁻² over 4 h days 3 and 4. MTX was given as follows, depending on GFR: >120 ml min⁻¹, 2 g m⁻² loading then 8 g m⁻² over 12 h (use 6g m⁻² over 12 h if >30 years or PS>1); 100–119 ml min⁻¹, 2 g m⁻² loading, then 6 g m⁻² over 12 h; 80–99 ml min⁻¹, 2 g m⁻² loading, then 4 g m⁻² over 12 h; 60–79 ml min⁻¹, 2 g m⁻² loading, then 3 g m⁻² over 12 h; 40–59 ml min⁻¹, 1.5 g m⁻² loading followed by 2 g m⁻² over 12 h; 20–39 ml min⁻¹, 1 g m⁻² loading only. Acetazolamide was prescribed 500 mg 2 × per day for 3 days. Regular sodium bicarbonate (100 mmol), 6 h with 20 mmol KCl in 5% glucose for 48 h. Folinic acid was started 30 h post-MTX treatment. Folinic acid: rescue commenced at 30 h post-MTX treatment. The first level of MTX was taken 24 h post-infusion start. Initial rescue was 100 mg i.v. over 30 min, followed by 250 mg over 24 h. If the 24-h level was <2 μmol l⁻¹ continue with folinic acid 30 mg, six hourly for 3 days, otherwise give a further infusion of 350 mg over 24 h and recheck level at 48 h. If the 24 h level >40μmol l⁻¹ the folinic acid was increased to 700 mg per 24 h. At 48 h and beyond: if the level were >3 μ l⁻¹ in the presence of renal impairment, the use of carboxypeptidase was considered. If renal function was preserved, an infusion of 700 mg per 24 h was continued; if the level was >1 and <3μmol l⁻¹, 350 mg was given over 24 h, and the level was checked every 24 h. When the level was <1, the dose was reduced to 30 mg orally 4 × per day, until the level was <0.2 μ l⁻¹. Haematological parameters: filgrastim (300 mcg per day) was started on day 4 and continued until WBC>3. To start each cycle, it was necessary to have neutrophils>1 × 10⁹ l⁻¹ and platelets>60 × 10⁹ l⁻¹. Renal parameters: U and E and creatinine (Cr) were measured daily, and if Cr rose >20%, no cisplatin was given until Cr reduced below that level. If the serum creatinine rose clearance by 15%, an EDTA clearance was repeated. If the clearance was <40 ml min⁻¹, carboplatin AUC 4 was substituted for cisplatin. In this case, vincristine was given on weeks 2, 4, 7 and 9. If the clearance subsequently improved, then cisplatin was reintroduced and vincristine was dropped. Dose reductions: a 20% dose reduction was made in the doses of cisplatin, actinomycin-D and etoposide, in the presence of platelets<20 × 10⁹ l⁻¹ or neutrophils<0.5 × 10⁹ l⁻¹ for>5 days. A 20% reduction in the dose of MTX was made in the presence of grade 3 or 4 mucositis. A 50% dose reduction in the dose of MTX was made, if the 24-h level was >80 μ l⁻¹ or the 48 h level was >4 μ l⁻¹.

Figure 2

Overall survival.

Figure 3

PFS in pretreated patients by absence or presence of raised LDH.

Figure 4

PFS in pretreated patients by age (above and below median).

Figure 5

PFS by Memorial Sloan-Kettering Risk Group.

Figure 6

PFS in pretreated patients by dose density over cycles 1 and 2.