A randomized phase II trial of induction chemotherapy followed by cisplatin chronotherapy versus constant rate delivery combined with radiotherapy

Abstract

Chronotherapy is no longer a novel concept in cancer treatment after approximately 20 years of development. Many clinical trials have provided strong supporting evidence that chronomodulated treatment yields better results than a traditional dosage regimen. This study aimed to evaluate the adverse reactions, effect on immune functions, and therapeutic efficacy of chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) combined with intensity-modulated radiation therapy (IMRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 148 patients with biopsy-diagnosed untreated stage III-IVb NPC were randomly assigned to undergo two cycles of chronomodulated infusion (study group) or flat intermittent infusion (control group) of DDP (100 mg/m2 on day 1, 21 days/cycle) synchronized with radical radiotherapy. Patients in the study group received chronomodulated infusion, with peak delivery of DDP at 16:00 pm. Patients in the control group received a routine constant rate of infusion. Both groups were treated with the same radiotherapy techniques. Over a median follow-up of 20 months, the study group had better outcomes for adverse effects and immune functions compared with the control group. During the phase of concurrent chemoradiotherapy, the incidence of nausea, vomiting, and oral mucositis in the study and control groups was 66.7% and 79.5% (p < 0.05), 47.9% and 71.2% (p < 0.05), and 73.9% and 87.7% (p < 0.05), respectively. There was no significant difference in 2-year overall survival, progression-free survival, and distant metastasis-free survival between the two groups (p > 0.05). Chronochemotherapy significantly reduced the incidence of adverse reactions and enhanced the tolerance for treatment without affecting survival. It is worth mentioning that reduced destruction of immune function is a novel area of exploration in chronotherapy research.

Exploiting the Circadian Clock for Improved Cancer Therapy: Perspective From a Cell Biologist

“…These resistance mechanisms emerge from processes that are controlled by the circadian clock (Sancar et al, 2010;Dallmann et al, 2014;Dallmann et al, 2016). Thus far, clinical studies have shown that several adverse effects experienced by cancer patients taking cisplatin-based chemotherapy decreases when cisplatin is applied in a chrono-modulated context (Li et al, 2015;Zhang et al, 2017). The results and outcomes of these studies indicate that the proper timing of drug administration reduces cisplatin-induced adverse effects in patients.…”

Circadian Variation in Efficacy of Medications

“…[247][248][249] Recent studies in the field of cancer chronotherapy have examined chronomodulated variable rate infusions of docetaxel, cisplatin, or 5-FU with or without radiotherapy for the treatment of advanced nasopharyngeal carcinoma. [250][251][252][253][254][255] Chronomodulated variable rate infusions of chemotherapeutics resulted in less adverse effects [250][251][252][253]255 and improved cellular immune numbers in virtually all clinical trials. [250][251][252]254,255 Few studies have examined the effects of chronomodulated oral chemotherapy treatment.…”

“…[250][251][252][253][254][255] Chronomodulated variable rate infusions of chemotherapeutics resulted in less adverse effects [250][251][252][253]255 and improved cellular immune numbers in virtually all clinical trials. [250][251][252]254,255 Few studies have examined the effects of chronomodulated oral chemotherapy treatment. [256][257][258] One such retrospective study compared the effects of morning with evening dosing of 6-mercaptopurine and methotrexate for the treatment of childhood acute lymphoblastic leukemia in 118 children and reported that evening dosing increased disease-free survival and reduced the risk of relapse by 2.5 times.…”

From sleep medicine to medicine during sleep: a new paradigm

“…However, despite decades of intense research of circadian rhythm in cancer, chronotherapy has had limited impact on the mainstream clinical oncology 75 . This might be explained by its failure to show significant improvement in overall survival in previous large clinical trials [76][77][78] . However, at the same time, positive effects of nocturnal chemotherapy on toxicity and tolerability have been demonstrated for almost all types of chemotherapeutic drugs, including: 5-fluorouracil, irinotecan, doxorubicin and most platinum-based drugs [79][80][81][82] .…”