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Concurrent weekly single cisplatin vs triweekly cisplatin alone

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Harihar Nath Tiwari

This document summarizes a meta-analysis comparing weekly vs triweekly cisplatin chemotherapy with radiotherapy for locally advanced cervical cancer. The analysis found no significant difference in 5-year overall survival or distant recurrence rates between the two regimens. However, the triweekly regimen was associated with higher treatment compliance and a higher risk of leucopenia as an acute adverse effect. In conclusion, triweekly cisplatin appeared superior for local recurrence and treatment compliance.

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Concurrent weekly single cisplatin vs triweekly cisplatin alone with radiotherapy for treatment of locally advanced cervical cancer: a meta-analysis DR. HARIHAR(DNB RT)
Introduction Cervical cancer (CC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer deaths among women worldwide. An estimated 90% of deaths from CC occur in the developing countries. The application of human papilloma virus vaccine and advances in screening technology have contributed to the great achievements in prevention and treatment of CC and premalignant disease; however, the worldwide survival and prognosis of this malignancy is still very poor, especially for locally advanced cervical carcinoma (LACC). Based on favorable outcomes in 5 randomized clinical trials (RCTs), cisplatin (CDDP)-based chemo radiotherapy is strongly recommended for patients with LACC who require radiotherapy (RT)
A 2005 update of a meta-analysis of concomitant chemotherapy and radiationtherapy found 24 trials and concluded that chemoradiation improves overall survival and PFS, whether or not cisplatin was used, with absolute benefits of 10% and 13%, respectively.Similarly, a 2008 meta-analysis of the 13 trials that compared chemoradiotherapy to radiation found that there was a 6% improvement in 5-year survival with concurrent chemoradiation (HR 0.81, P <.001). The effect was attributed to a reduction in both local and distant recurrence. Chemoradiation increased acute hematologic and gastrointestinal toxicity, but no confirmation was made about a difference in late toxicity.
Concurrent weekly single cisplatin vs triweekly cisplatin alone
Background Radiotherapy (RT) concurrent with cisplatin (CDDP) is the standard regimen used for treatment of locally advanced cervical carcinoma. In this meta-analysis, This study compared the weekly and triweekly single CDDP concomitant chemoradiation regimens for treatment of cervical cancer with respect to compliance, recurrence, survival, and acute adverse effects.
Materials and methods A systematic search for relevant studies was conducted in PubMed, Cochrane Library, EMBASE, and Medline databases. Fixed- or random-effects model was used for pooled analysis. The end points were overall survival, recurrence, compliance, and acute adverse effect reported as odds ratios (ORs) and 95% CI.
Search strategy Only those studies published from 1990 to December 29, 2017 in English were considered.
Furthermore, weekly CDDP regimen concurrent with radiation is widely accepted due to better compliance and low toxicity, compared with tri weekly CDDP plus 5- fluorouracil (5-FU) regimen among these 5 studies. In a study by Lanciano et al, outcomes in the 5-FU treatment arm were not superior to those in the weekly CDDP arm.
Hu et al conducted a meta-analysis to evaluate the efficacy of weekly and tri weekly CDDP with RT for treatment of CC. They found that weekly CDDP was associated with a lower risk of hematological toxicity compared with the tri weekly CDDP with CCRT. However, the 2 regimens were comparable with respect to PFS and OS (P>0.05), which is similar to the results of another meta-analysis conducted by Chen et al.
Several recent studies have compared the 2 different single CDDP schedules with respect to survival and incidence of adverse events. Ryu et al found tri weekly CDDP CCRT had better 5-year OS and higher relatively completion rate of scheduled chemotherapy cycles, but less severe neutropenia compared with the conventional weekly CDDP regimen.
outcomes of weekly CDDP regimen for CCRT were found to be better with respect to hematological toxicity in a study conducted by Kinjyo et al in 2017. No definitive conclusions were drawn from these studies. Therefore, 6 randomized trials and 2 retrospective studies were included in this meta-analysis to explore the difference between the different CDDP- alone regimens for patients with LACC.
Concurrent weekly single cisplatin vs triweekly cisplatin alone
Inclusion and exclusion criteria Studies were included in the analysis if: 1) they were randomized controlled trials or retrospective studies that compared tri weekly single CDDP plus RT plus vs weekly single CDDP plus RT; 2) no evidence of para-aortic lymph node or distant metastasis on pretreatment imaging (stages IIVA); and 3) the long-term OS and recurrence rate, including local and distance, were assessed as outcomes to measure the effect of the treatment.
Studies were excluded if patients had previous histories of chemotherapy or RT, or other factors seriously affecting the survival and treatment processes.
Statistical analysis OS and recurrence rate, including the locoregional relapse rate and rate of distant metastasis were the primary end points, and appliance, acute adverse were secondary end points.
Study selection and characteristics
Primary end points: 5-year OS and recurrence rate The analysis revealed no statistically significant difference between the tri weekly and weekly regimens of CDDP-based chemotherapy plus RT with respect to 5-year OS (OR, 0.63; 95% CI: 0.321.23; P=0.17;
Concurrent weekly single cisplatin vs triweekly cisplatin alone
Concurrent weekly single cisplatin vs triweekly cisplatin alone
For the meta-analysis of recurrence rate (n=4 studies),no significant heterogeneity was observed among the trials. The study by Einstein et al showed no significant difference between the 2 regimens of CCRT with respect to 3-year recurrence (P=0.11).
no significant difference was observed between the 2 regimens of CCRT with respect to 5-year distant recurrence (OR, 1.15; 95% CI: 0.721.84; P=0.57;
Concurrent weekly single cisplatin vs triweekly cisplatin alone
Secondary end points: compliance and acute adverse events Not completing the total cycles of chemotherapy or missing any dose of CDDP or delaying radiation period longer than a certain period of time, varieties existed in different studies, was defined as patients with bad compliance.
meta-analysis of compliance (n=5 studies) determined that triweekly CDDP plus RT was associated with a 14% increased risk of compliance compared with weekly CDDPbased CT plus RT (OR, 0.49; 95% CI: 0.290.83; P=0.009;Figure 5).
Concurrent weekly single cisplatin vs triweekly cisplatin alone
We only chose 2 and 3 trials for the meta- analysis of leucopenia and vomiting respectively, for assessment of acute adverse events . Tri weekly CDDP plus RT was associated with a 100% increased risk of leucopenia compared with weekly CDDP-based CT plus RT (OR, 0.30; 95% CI: 0.100.92; P=0.03; Figure 6).
NO significant difference was observed between the 2 regimens of CDDP-based CCRT with respect to incidence of vomiting (OR, 1.14; 95% CI: 0.602.15; P=0.69; Figure 6).
Concurrent weekly single cisplatin vs triweekly cisplatin alone
Discussion Weekly CDDP treatment regimen was recommended by National Comprehensive Cancer Network guidelines, based on the results of 5 randomized trials 26 conducted during the 1990s. However, in an RCT by Ryu et al triweekly single CDDP chemotherapy concurrent with RT was associated with better 5-year survival and lower incidence of hematological toxicity compared with the conventional weekly CDDP in patients with LACC.
Two meta-analyses compared concurrent weekly CDDP vs tri weekly CDDP in combination with RT for treatment of CC. Both these meta-analyses suggested the superiority of weekly CDDP regimen based only on the lower incidence of hematological toxicity. In this meta-analysis, we found that tri weekly CDDP (20mg/m2 for 5 days or 75 mg/m2) alone combined with RT was associated with a lower rate of local recurrence and better compliance compared with weekly CDDP (40 mg/m2) plus RT in patients with LACC.
The incidence of hematological toxicity was higher in the tri weekly CDDP arm, which is similar to the findings of a previous meta- analysis. Besides, the 5-year OS was relatively better in the tri weekly CDDP arm (P=0.06).
In our meta-analysis, we found a higher treatment completion rate among patients treated with tri weekly CDDP regimen. Our findings with respect to treatment compliance are consistent with that of Einstein et al however, tri weekly CDDP regimen was largely used for hospitalized patients with poor general physical condition, while outpatients with good physical condition always received weekly CDDP regimen
In the study by Nagy, 5-year local relapse-free survival in the triweekly arm (87%) was significantly superior than that in the weekly CDDP arm (77%) (P<0.01). No statistically significant differences were observed with respect to OS (QW vs Q3W; 72% vs 78%; P=0.14) and disease-free survival (DFS) (QW vs Q3W;69% vs 73%; P=0.09).
limitations Pelvic radiation therapy in patients with CC may cause acute radiation enteritis, radio- cystitis, and radio dermatitis. Severe diarrhea and urinary tract symptoms may also delay the treatment process. we only selected leucopenia and vomiting as the parameters for assessment of side effects of CCRT.
Differences with respect to dose and duration of RT may also have influenced our results.
this is the first systematic review that compares the efficiency and adverse events associated with single agent tri weekly CDDP plus RT and weekly CDDP alone plus concurrent RT in patients with LACC. We found that the lower rate of local relapse and the tendency for better OS probably occurs at the cost of more side effects.
Conclusion: Tri weekly single platinum chemotherapy plus concurrent RT was superior to weekly CDDP regimen with respect to local recurrence and treatment compliance in patients with locally advanced cervical carcinoma. It may be concluded from this study that there is no statistically significant difference in tumor control, hematological, upper gastrointestinal and lower gastrointestinal toxicities when concomitant chemo-radiation with cisplatin is given either three weekly or weekly.

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Concurrent weekly single cisplatin vs triweekly cisplatin alone

  • 1. Concurrent weekly single cisplatin vs triweekly cisplatin alone with radiotherapy for treatment of locally advanced cervical cancer: a meta-analysis DR. HARIHAR(DNB RT)
  • 2. Introduction Cervical cancer (CC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer deaths among women worldwide. An estimated 90% of deaths from CC occur in the developing countries. The application of human papilloma virus vaccine and advances in screening technology have contributed to the great achievements in prevention and treatment of CC and premalignant disease; however, the worldwide survival and prognosis of this malignancy is still very poor, especially for locally advanced cervical carcinoma (LACC). Based on favorable outcomes in 5 randomized clinical trials (RCTs), cisplatin (CDDP)-based chemo radiotherapy is strongly recommended for patients with LACC who require radiotherapy (RT)
  • 3. A 2005 update of a meta-analysis of concomitant chemotherapy and radiationtherapy found 24 trials and concluded that chemoradiation improves overall survival and PFS, whether or not cisplatin was used, with absolute benefits of 10% and 13%, respectively.Similarly, a 2008 meta-analysis of the 13 trials that compared chemoradiotherapy to radiation found that there was a 6% improvement in 5-year survival with concurrent chemoradiation (HR 0.81, P <.001). The effect was attributed to a reduction in both local and distant recurrence. Chemoradiation increased acute hematologic and gastrointestinal toxicity, but no confirmation was made about a difference in late toxicity.
  • 5. Background Radiotherapy (RT) concurrent with cisplatin (CDDP) is the standard regimen used for treatment of locally advanced cervical carcinoma. In this meta-analysis, This study compared the weekly and triweekly single CDDP concomitant chemoradiation regimens for treatment of cervical cancer with respect to compliance, recurrence, survival, and acute adverse effects.
  • 6. Materials and methods A systematic search for relevant studies was conducted in PubMed, Cochrane Library, EMBASE, and Medline databases. Fixed- or random-effects model was used for pooled analysis. The end points were overall survival, recurrence, compliance, and acute adverse effect reported as odds ratios (ORs) and 95% CI.
  • 7. Search strategy Only those studies published from 1990 to December 29, 2017 in English were considered.
  • 8. Furthermore, weekly CDDP regimen concurrent with radiation is widely accepted due to better compliance and low toxicity, compared with tri weekly CDDP plus 5- fluorouracil (5-FU) regimen among these 5 studies. In a study by Lanciano et al, outcomes in the 5-FU treatment arm were not superior to those in the weekly CDDP arm.
  • 9. Hu et al conducted a meta-analysis to evaluate the efficacy of weekly and tri weekly CDDP with RT for treatment of CC. They found that weekly CDDP was associated with a lower risk of hematological toxicity compared with the tri weekly CDDP with CCRT. However, the 2 regimens were comparable with respect to PFS and OS (P>0.05), which is similar to the results of another meta-analysis conducted by Chen et al.
  • 10. Several recent studies have compared the 2 different single CDDP schedules with respect to survival and incidence of adverse events. Ryu et al found tri weekly CDDP CCRT had better 5-year OS and higher relatively completion rate of scheduled chemotherapy cycles, but less severe neutropenia compared with the conventional weekly CDDP regimen.
  • 11. outcomes of weekly CDDP regimen for CCRT were found to be better with respect to hematological toxicity in a study conducted by Kinjyo et al in 2017. No definitive conclusions were drawn from these studies. Therefore, 6 randomized trials and 2 retrospective studies were included in this meta-analysis to explore the difference between the different CDDP- alone regimens for patients with LACC.
  • 13. Inclusion and exclusion criteria Studies were included in the analysis if: 1) they were randomized controlled trials or retrospective studies that compared tri weekly single CDDP plus RT plus vs weekly single CDDP plus RT; 2) no evidence of para-aortic lymph node or distant metastasis on pretreatment imaging (stages IIVA); and 3) the long-term OS and recurrence rate, including local and distance, were assessed as outcomes to measure the effect of the treatment.
  • 14. Studies were excluded if patients had previous histories of chemotherapy or RT, or other factors seriously affecting the survival and treatment processes.
  • 15. Statistical analysis OS and recurrence rate, including the locoregional relapse rate and rate of distant metastasis were the primary end points, and appliance, acute adverse were secondary end points.
  • 16. Study selection and characteristics
  • 17. Primary end points: 5-year OS and recurrence rate The analysis revealed no statistically significant difference between the tri weekly and weekly regimens of CDDP-based chemotherapy plus RT with respect to 5-year OS (OR, 0.63; 95% CI: 0.321.23; P=0.17;
  • 20. For the meta-analysis of recurrence rate (n=4 studies),no significant heterogeneity was observed among the trials. The study by Einstein et al showed no significant difference between the 2 regimens of CCRT with respect to 3-year recurrence (P=0.11).
  • 21. no significant difference was observed between the 2 regimens of CCRT with respect to 5-year distant recurrence (OR, 1.15; 95% CI: 0.721.84; P=0.57;
  • 23. Secondary end points: compliance and acute adverse events Not completing the total cycles of chemotherapy or missing any dose of CDDP or delaying radiation period longer than a certain period of time, varieties existed in different studies, was defined as patients with bad compliance.
  • 24. meta-analysis of compliance (n=5 studies) determined that triweekly CDDP plus RT was associated with a 14% increased risk of compliance compared with weekly CDDPbased CT plus RT (OR, 0.49; 95% CI: 0.290.83; P=0.009;Figure 5).
  • 26. We only chose 2 and 3 trials for the meta- analysis of leucopenia and vomiting respectively, for assessment of acute adverse events . Tri weekly CDDP plus RT was associated with a 100% increased risk of leucopenia compared with weekly CDDP-based CT plus RT (OR, 0.30; 95% CI: 0.100.92; P=0.03; Figure 6).
  • 27. NO significant difference was observed between the 2 regimens of CDDP-based CCRT with respect to incidence of vomiting (OR, 1.14; 95% CI: 0.602.15; P=0.69; Figure 6).
  • 29. Discussion Weekly CDDP treatment regimen was recommended by National Comprehensive Cancer Network guidelines, based on the results of 5 randomized trials 26 conducted during the 1990s. However, in an RCT by Ryu et al triweekly single CDDP chemotherapy concurrent with RT was associated with better 5-year survival and lower incidence of hematological toxicity compared with the conventional weekly CDDP in patients with LACC.
  • 30. Two meta-analyses compared concurrent weekly CDDP vs tri weekly CDDP in combination with RT for treatment of CC. Both these meta-analyses suggested the superiority of weekly CDDP regimen based only on the lower incidence of hematological toxicity. In this meta-analysis, we found that tri weekly CDDP (20mg/m2 for 5 days or 75 mg/m2) alone combined with RT was associated with a lower rate of local recurrence and better compliance compared with weekly CDDP (40 mg/m2) plus RT in patients with LACC.
  • 31. The incidence of hematological toxicity was higher in the tri weekly CDDP arm, which is similar to the findings of a previous meta- analysis. Besides, the 5-year OS was relatively better in the tri weekly CDDP arm (P=0.06).
  • 32. In our meta-analysis, we found a higher treatment completion rate among patients treated with tri weekly CDDP regimen. Our findings with respect to treatment compliance are consistent with that of Einstein et al however, tri weekly CDDP regimen was largely used for hospitalized patients with poor general physical condition, while outpatients with good physical condition always received weekly CDDP regimen
  • 33. In the study by Nagy, 5-year local relapse-free survival in the triweekly arm (87%) was significantly superior than that in the weekly CDDP arm (77%) (P<0.01). No statistically significant differences were observed with respect to OS (QW vs Q3W; 72% vs 78%; P=0.14) and disease-free survival (DFS) (QW vs Q3W;69% vs 73%; P=0.09).
  • 34. limitations Pelvic radiation therapy in patients with CC may cause acute radiation enteritis, radio- cystitis, and radio dermatitis. Severe diarrhea and urinary tract symptoms may also delay the treatment process. we only selected leucopenia and vomiting as the parameters for assessment of side effects of CCRT.
  • 35. Differences with respect to dose and duration of RT may also have influenced our results.
  • 36. this is the first systematic review that compares the efficiency and adverse events associated with single agent tri weekly CDDP plus RT and weekly CDDP alone plus concurrent RT in patients with LACC. We found that the lower rate of local relapse and the tendency for better OS probably occurs at the cost of more side effects.
  • 37. Conclusion: Tri weekly single platinum chemotherapy plus concurrent RT was superior to weekly CDDP regimen with respect to local recurrence and treatment compliance in patients with locally advanced cervical carcinoma. It may be concluded from this study that there is no statistically significant difference in tumor control, hematological, upper gastrointestinal and lower gastrointestinal toxicities when concomitant chemo-radiation with cisplatin is given either three weekly or weekly.