BACKGROUND. Bortezomib is active in heavily pretreated multiple myeloma patients; the dose‐limiting toxicity is peripheral neuropathy (PN). METHODS. The authors retrospectively reviewed the incidence, severity, and risk factors for PN in 78 patients who received bortezomib. The median age was 57 years (range, 33–80 years), 62% of patients were men, and 37% of patients were African Americans. Seventeen patients (22%) had diabetes mellitus (DM), and 66 patients (85%) had received thalidomide. Before bortezomib treatment, 37% of the patients reported subjective, grade 1 or 2 PN. Patients received bortezomib alone (n = 10 patients) plus dexamethasone (n = 36 patients) and thalidomide (n = 20 patients) or chemotherapy (n = 12 patients). PN affected 52% of patients, including grade 3 and 4 PN in 15% and 7%, respectively. RESULTS. Twelve patients stopped bortezomib because of side effects that included PN (n = 9 patients), diarrhea (n = 2 patients) and cytomegalovirus pneumonia (n = 1 patient); 11 patients had dose reductions because of PN. Grade 4 PN affected 6 patients (sensory, n = 4 patients; motor/sensory, n = 2 patients). The onset of grade 4 PN was sudden rather than cumulative. Factors that were predictive of PN grade were baseline PN (P = .002), prior thalidomide use (P = .03), and the presence of DM (P = .03). Multiple myeloma responses included complete, near complete, and partial responses in 5% of patients, 10% of patients, and 27% of patients, respectively. Responses were independent of PN and of whether bortezomib was combined with chemotherapy or thalidomide. Patients remained on therapy longer for a median of 5 cycles (range, 2–36 cycles) when they received bortezomib plus thalidomide versus 3 cycles (range, 1–19 cycles) for the other combinations. PN therapy was mostly supportive. It was noteworthy that 6 of 9 patients with PN who received lenalidomide as salvage therapy after bortezomib had significant improvement in their symptoms. CONCLUSIONS. The risk of bortezomib‐related PN was greater in patients who had PN and DM at baseline. The authors concluded that an unexpected, symptomatic improvement of PN on lenalidomide is worth further investigation. Cancer 2007. © 2007 American Cancer Society.
Background: Histologically documented cases of parvoviral myocarditis are exceedingly rare.
Platinum-based therapy is active in advanced head and neck squamous cell carcinoma (HNSCC). Patients with inoperable recurrent or metastatic HNSCC have a poor prognosis; many have difficulty tolerating cisplatin-based regimens. Oxaliplatin has antitumor activity without many of the toxicities of cisplatin. We conducted a phase I pilot study to investigate the dose limitation of oxaliplatin with 5-fluorouracil (5-FU) and cetuximab in patients with untreated recurrent or metastatic HNSCC. The planned dose escalation schedule included: dose level 1: oxaliplatin 100 mg/m(2) day 1, 5-FU CIV 750 mg/m(2)/day over 96 h beginning day 1, and cetuximab 400 mg/m(2) day 1 (then 250 mg/m(2) weekly) every 21 days. Dose level 2: oxaliplatin 130 mg/m(2) day 1, 5-FU CIV 1,000 mg/m(2)/day over 96 h beginning day 1, and the same dose and schedule of cetuximab. Seven patients were accrued at dose level 1 and three at dose level 2. Dose level 1 toxicity included grade 1-2 stomatitis, fatigue, acneiform rash, and anemia, and grade 1 nausea and transaminitis. Dose level 2 toxicity was unacceptable: 2 of 3 patients experienced grade 4 toxicities (stomatitis, diarrhea, and acute renal failure) requiring hospitalization with one treatment-related death. Accrual was therefore closed with dose level 1 considered the maximum tolerated dose. Observed responses were short-lived. The regimen of oxaliplatin 100 mg/m(2) day 1, infusional 5-FU 750 mg/m(2)/day over 96 h beginning day 1, and cetuximab 400 mg/m(2) day 1 (then 250 mg/m(2) weekly), every 21 days, has manageable toxicity; these doses are recommended for phase II evaluation in the treatment for unresectable or metastatic HNSCC.
Bortezomib has demonstrated activity in heavily pretreated MM patients. The dose limiting toxicity is peripheral neuropathy (PN) that affects up to 35% of the patients (Richardson et al JCO 2006). We retrospectively reviewed the incidence and severity of PN in 78 patients who received bortezomib at our institution. The median age was 57 years (range: 33–80), 62% were men, and 37% were African Americans (AA). Risk factors for PN included prior use of thalidomide in 53 patients (68%) and vincristine in 31 patients (40%). Seventeen patients (22%) had diabetes mellitus. Before bortezomib treatment 29 patients (37%) reported subjective grade 1–2 PN. Patients received bortezomib alone (n=10) or in combination with dexamethasone (n=36) and thalidomide (n=20) or chemotherapy (n=12). Responses included complete, near complete and partial responses in 5%, 10% and 27%, respectively. Grade 2 and higher PN occurred in 52% of the patients including Grade grades 3 and 4 PN in 15% and 7%, respectively. Twelve patients stopped bortezomib due to side effects that included PN (n=8), diarrhea (n=2) and CMV pneumonia (n=1), and 11 patients had dose reductions because of PN and fatigue. Grade 4 PN affected 6 patients (sensory n=4, and motor/sensory, n=2), 5 of whom were AA and 4 of whom had DM. The onset of grade 4 PN was acute rather than cumulative as noted with lower grades and took a median of 8 months (range: 4–16+) to improve compared to 3–4 months for lower grade PN. Neuropathy grade was not associated with age, sex, race or renal function (10 patients had creatinine > 2 mg/dl, including 2 on dialysis). Factors predictive of PN were baseline neuropathy (p=0.002) in addition to prior thalidomide use (p=0.03) and presence of DM (p=0.03). Responses were independent of neuropathy grade and whether bortezomib was combined with chemotherapy or thalidomide. The duration of therapy in responding patients was longer in patients receiving bortezomib in combination with thalidomide with a median of 5 cycles (range: 2–36) versus those who received other bortezomib combinations 3 cycles (range 1–19). Two of four patients with grade 4 sensory PN had their best response ever after 3 cycles of bortezomib; both had failed transplant and thalidomide based therapies; one remains in continuous complete remission for 24 months. PN therapy was mostly supportive including combinations of analgesics duloxetine, gabapentin, and pregabalin. Interestingly, 6 of 9 patients with PN who received lenalidomide as salvage therapy after progression on bortezomib had significant improvement in their symptoms; 3 of them stopped analgesics. In conclusion, the highest risk and grade of bortezomib neurotoxicity was seen in patients with baseline PN secondary to prior thalidomide use and DM. On the other hand, responding patients who received bortezomib in combination with thalidomide remained longer on therapy with minimal dose reductions. Although this may represent a section bias it is possible that thalidomide’s known anti-inflammatory and anti-angiogenesis properties protect against bortezomib-induced PN. Similar effects may explain the unexpected symptomatic improvement of PN on lenalidomide.
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