Bevacizumab-enhanced chemo ‘new standard’ in metastatic cervical cancer

PARIS – Although survival remains relatively poor, the options for the management of metastatic, recurrent, or persistent cervical cancer have increased in recent years, with bevacizumab-enhanced, platinum-based, combination chemotherapy becoming the “new standard” for many women according to medical oncologist Isabelle Ray-Coquard.

Speaking at a recent international conference on anticancer treatment, Dr. Ray-Coquard of Centre Léon Bérard in Lyon, France, noted that there are several questions that the medical oncologists must address before prescribing treatment. These are: Would the patient benefit from chemotherapy and if so, should a single-agent or a combination be used? Is the patient a candidate for a new or novel agent? Or would palliative care be the best option? How can patients best be selected for treatment?

“We have some strong data to support the use of cisplatin first line,” she observed. “Cisplatin is probably the first actor in the management of cervix cancer.” Response rates using single-agent cisplatin have ranged from 18% to 25% in women with recurrent and advanced carcinoma of the cervix.

“The question is what is the best partner for cisplatin?” Dr. Ray-Coquard asked. She highlighted several studies showing the activity of other cytotoxic chemotherapies as single agents, with the highest responses seen with paclitaxel (Taxol, at 19% of patients), followed by vinorelbine (Navelbine, 18%), irinotecan (Campto, 17%), topotecan (Hycamtin, 16%), docetaxel (Taxotere, 13%), and the lowest with gemcitabine (Gemzar, 8%).

Both paclitaxel and topotecan have been studied in combination with cisplatin vs. cisplatin alone and been shown to confer survival benefits. In the Gynecologic Oncology Group (GOG) 169 study (J. Clin. Oncol. 2004;22:3113-9), for example, paclitaxel plus cisplatin was associated with a significant (P < .001) increase in progression-free survival (PFS) of 4.8 vs. 2.8 months, although overall survival (OS) was not statistically different (9.7 vs. 8.8 months). Dr. Ray-Coquard noted, however, that paclitaxel had been given to women randomized to cisplatin at relapse, which might have clouded the OS benefit.

Similar benefits were seen when topotecan and cisplatin were combined and compared against single agent cisplatin in the GOG 179 study (J. Clin. Oncol. 2005;23:4626-33), with median PFS of 4.6 vs 2.9 months (P = .014) and median OS of 9.4 and 6.5 months (P = .017).

The toxicity of combining chemotherapies is important, and looking at the combination of topotecan and cisplatin vs. cisplatin alone in the GOG 179 study, Dr. Ray-Coquard noted that grade 3 & 4 side effects such as neutropenia, thrombocytopenia, nausea, and vomiting occurred much more frequently.

Data from the GOG 204 study (J. Clin. Oncol. 2009;27:4649-55) suggested that both paclitaxel and topotecan were good partners for cisplatin, with perhaps an advantage for paclitaxel. The latter combination can be inconvenient for patients, however, as it requires infusion of paclitaxel over 24 hours and hydration is required to prevent renal toxicity associated with the cisplatin. The combination is also quite toxic and hasn’t been shown to significantly relieve pain or to improve quality of life.

Phase II trial findings (Gynecol. Oncol. 2012;125:307-11) suggest that carboplatin might be an effective and less toxic alternative to cisplatin in combination with paclitaxel. There may also be a slight advantage of using carboplatin in patients who have already received prior platinum therapy but not in those who have not received cisplatin before.

“If we want to increase the overall survival, we need to also explore new compounds,” Dr. Ray-Coquard said. Drugs targeting the human epidermal growth factor receptor (HER) and angiogenesis have been tested, with lapatinib (Tykerb) and pazopanib (Votrient) found to be too toxic to use in combination but perhaps have an effect on survival when used alone. Cediranib (tentative trade name Recentin) in combination with paclitaxel and cisplatin also improved PFS in a phase II trial.

The best evidence in support of using targeted therapy to date is for bevacizumab. Using bevacizumab in combination with platinum-based combination chemotherapy is supported by the positive findings of the GOG 240 study (N. Engl. J. Med. 2014;370:734-43). This trial tested two hypotheses: first, if a nonplatinum chemotherapy doublet of paclitaxel and topotecan (Hycamtin) would be better than a platinum-based couplet (cisplatin plus paclitaxel); second if receiving additional antiangiogenic therapy with bevacizumab (Avastin) would confer any benefit over these combined chemotherapy regimens.

The results showed that combining topotecan with paclitaxel was not superior to cisplatin plus paclitaxel. When bevacizumab was combined with chemotherapy, however, there were PFS and OS benefits. Bevacizumab conferred an almost 4-month gain in OS, Dr. Ray-Coquard said.

Several factors including age, performance status, and previous treatment and toxicities need to be considered when selecting this or other treatment, she explained in an interview.

Women who have a very poor (≥ 2) performance status or who are symptomatic may not be suitable for the bevacizumab-enhanced therapy, as they may not be able to tolerate the toxicities associated with this regimen.

Notable toxicities reported with the regimen in the GOG 240 study included gastrointestinal fistula and perforation, neutropenia, including febrile neutropenia, hypertension, thrombosis and an increased risk for bleeding in the GI tract.

Understandably, care needs to be taken when considering this regimen for women who may have residual toxicity from other treatments, such as enteritis or cystitis caused by radiotherapy, and those with bowel, bladder, or vaginal involvement.

Women with vaginal bleeding or renal impairment may also not be able to tolerate combined antiangiogenic and chemotherapeutic treatment very well, and women with uncontrolled hypertension might not be good candidates.

Perhaps some of these women could still receive platinum-based chemotherapy without the bevacizumab, but, unfortunately, there will still be women for whom best supportive or palliative care may be the only option, Dr. Ray-Coquard said.

Dr. Ray-Coquard has served on advisory boards convened by Roche and AstraZeneca.

PARIS – Although survival remains relatively poor, the options for the management of metastatic, recurrent, or persistent cervical cancer have increased in recent years, with bevacizumab-enhanced, platinum-based, combination chemotherapy becoming the “new standard” for many women according to medical oncologist Isabelle Ray-Coquard.

Speaking at a recent international conference on anticancer treatment, Dr. Ray-Coquard of Centre Léon Bérard in Lyon, France, noted that there are several questions that the medical oncologists must address before prescribing treatment. These are: Would the patient benefit from chemotherapy and if so, should a single-agent or a combination be used? Is the patient a candidate for a new or novel agent? Or would palliative care be the best option? How can patients best be selected for treatment?

“We have some strong data to support the use of cisplatin first line,” she observed. “Cisplatin is probably the first actor in the management of cervix cancer.” Response rates using single-agent cisplatin have ranged from 18% to 25% in women with recurrent and advanced carcinoma of the cervix.

“The question is what is the best partner for cisplatin?” Dr. Ray-Coquard asked. She highlighted several studies showing the activity of other cytotoxic chemotherapies as single agents, with the highest responses seen with paclitaxel (Taxol, at 19% of patients), followed by vinorelbine (Navelbine, 18%), irinotecan (Campto, 17%), topotecan (Hycamtin, 16%), docetaxel (Taxotere, 13%), and the lowest with gemcitabine (Gemzar, 8%).

Both paclitaxel and topotecan have been studied in combination with cisplatin vs. cisplatin alone and been shown to confer survival benefits. In the Gynecologic Oncology Group (GOG) 169 study (J. Clin. Oncol. 2004;22:3113-9), for example, paclitaxel plus cisplatin was associated with a significant (P < .001) increase in progression-free survival (PFS) of 4.8 vs. 2.8 months, although overall survival (OS) was not statistically different (9.7 vs. 8.8 months). Dr. Ray-Coquard noted, however, that paclitaxel had been given to women randomized to cisplatin at relapse, which might have clouded the OS benefit.

Similar benefits were seen when topotecan and cisplatin were combined and compared against single agent cisplatin in the GOG 179 study (J. Clin. Oncol. 2005;23:4626-33), with median PFS of 4.6 vs 2.9 months (P = .014) and median OS of 9.4 and 6.5 months (P = .017).

The toxicity of combining chemotherapies is important, and looking at the combination of topotecan and cisplatin vs. cisplatin alone in the GOG 179 study, Dr. Ray-Coquard noted that grade 3 & 4 side effects such as neutropenia, thrombocytopenia, nausea, and vomiting occurred much more frequently.

Data from the GOG 204 study (J. Clin. Oncol. 2009;27:4649-55) suggested that both paclitaxel and topotecan were good partners for cisplatin, with perhaps an advantage for paclitaxel. The latter combination can be inconvenient for patients, however, as it requires infusion of paclitaxel over 24 hours and hydration is required to prevent renal toxicity associated with the cisplatin. The combination is also quite toxic and hasn’t been shown to significantly relieve pain or to improve quality of life.

Phase II trial findings (Gynecol. Oncol. 2012;125:307-11) suggest that carboplatin might be an effective and less toxic alternative to cisplatin in combination with paclitaxel. There may also be a slight advantage of using carboplatin in patients who have already received prior platinum therapy but not in those who have not received cisplatin before.

“If we want to increase the overall survival, we need to also explore new compounds,” Dr. Ray-Coquard said. Drugs targeting the human epidermal growth factor receptor (HER) and angiogenesis have been tested, with lapatinib (Tykerb) and pazopanib (Votrient) found to be too toxic to use in combination but perhaps have an effect on survival when used alone. Cediranib (tentative trade name Recentin) in combination with paclitaxel and cisplatin also improved PFS in a phase II trial.

The best evidence in support of using targeted therapy to date is for bevacizumab. Using bevacizumab in combination with platinum-based combination chemotherapy is supported by the positive findings of the GOG 240 study (N. Engl. J. Med. 2014;370:734-43). This trial tested two hypotheses: first, if a nonplatinum chemotherapy doublet of paclitaxel and topotecan (Hycamtin) would be better than a platinum-based couplet (cisplatin plus paclitaxel); second if receiving additional antiangiogenic therapy with bevacizumab (Avastin) would confer any benefit over these combined chemotherapy regimens.

The results showed that combining topotecan with paclitaxel was not superior to cisplatin plus paclitaxel. When bevacizumab was combined with chemotherapy, however, there were PFS and OS benefits. Bevacizumab conferred an almost 4-month gain in OS, Dr. Ray-Coquard said.

Several factors including age, performance status, and previous treatment and toxicities need to be considered when selecting this or other treatment, she explained in an interview.

Women who have a very poor (≥ 2) performance status or who are symptomatic may not be suitable for the bevacizumab-enhanced therapy, as they may not be able to tolerate the toxicities associated with this regimen.

Notable toxicities reported with the regimen in the GOG 240 study included gastrointestinal fistula and perforation, neutropenia, including febrile neutropenia, hypertension, thrombosis and an increased risk for bleeding in the GI tract.

Understandably, care needs to be taken when considering this regimen for women who may have residual toxicity from other treatments, such as enteritis or cystitis caused by radiotherapy, and those with bowel, bladder, or vaginal involvement.

Women with vaginal bleeding or renal impairment may also not be able to tolerate combined antiangiogenic and chemotherapeutic treatment very well, and women with uncontrolled hypertension might not be good candidates.

Perhaps some of these women could still receive platinum-based chemotherapy without the bevacizumab, but, unfortunately, there will still be women for whom best supportive or palliative care may be the only option, Dr. Ray-Coquard said.

Dr. Ray-Coquard has served on advisory boards convened by Roche and AstraZeneca.

PARIS – Although survival remains relatively poor, the options for the management of metastatic, recurrent, or persistent cervical cancer have increased in recent years, with bevacizumab-enhanced, platinum-based, combination chemotherapy becoming the “new standard” for many women according to medical oncologist Isabelle Ray-Coquard.

Speaking at a recent international conference on anticancer treatment, Dr. Ray-Coquard of Centre Léon Bérard in Lyon, France, noted that there are several questions that the medical oncologists must address before prescribing treatment. These are: Would the patient benefit from chemotherapy and if so, should a single-agent or a combination be used? Is the patient a candidate for a new or novel agent? Or would palliative care be the best option? How can patients best be selected for treatment?

“We have some strong data to support the use of cisplatin first line,” she observed. “Cisplatin is probably the first actor in the management of cervix cancer.” Response rates using single-agent cisplatin have ranged from 18% to 25% in women with recurrent and advanced carcinoma of the cervix.

“The question is what is the best partner for cisplatin?” Dr. Ray-Coquard asked. She highlighted several studies showing the activity of other cytotoxic chemotherapies as single agents, with the highest responses seen with paclitaxel (Taxol, at 19% of patients), followed by vinorelbine (Navelbine, 18%), irinotecan (Campto, 17%), topotecan (Hycamtin, 16%), docetaxel (Taxotere, 13%), and the lowest with gemcitabine (Gemzar, 8%).

Both paclitaxel and topotecan have been studied in combination with cisplatin vs. cisplatin alone and been shown to confer survival benefits. In the Gynecologic Oncology Group (GOG) 169 study (J. Clin. Oncol. 2004;22:3113-9), for example, paclitaxel plus cisplatin was associated with a significant (P < .001) increase in progression-free survival (PFS) of 4.8 vs. 2.8 months, although overall survival (OS) was not statistically different (9.7 vs. 8.8 months). Dr. Ray-Coquard noted, however, that paclitaxel had been given to women randomized to cisplatin at relapse, which might have clouded the OS benefit.

Similar benefits were seen when topotecan and cisplatin were combined and compared against single agent cisplatin in the GOG 179 study (J. Clin. Oncol. 2005;23:4626-33), with median PFS of 4.6 vs 2.9 months (P = .014) and median OS of 9.4 and 6.5 months (P = .017).

The toxicity of combining chemotherapies is important, and looking at the combination of topotecan and cisplatin vs. cisplatin alone in the GOG 179 study, Dr. Ray-Coquard noted that grade 3 & 4 side effects such as neutropenia, thrombocytopenia, nausea, and vomiting occurred much more frequently.

Data from the GOG 204 study (J. Clin. Oncol. 2009;27:4649-55) suggested that both paclitaxel and topotecan were good partners for cisplatin, with perhaps an advantage for paclitaxel. The latter combination can be inconvenient for patients, however, as it requires infusion of paclitaxel over 24 hours and hydration is required to prevent renal toxicity associated with the cisplatin. The combination is also quite toxic and hasn’t been shown to significantly relieve pain or to improve quality of life.

Phase II trial findings (Gynecol. Oncol. 2012;125:307-11) suggest that carboplatin might be an effective and less toxic alternative to cisplatin in combination with paclitaxel. There may also be a slight advantage of using carboplatin in patients who have already received prior platinum therapy but not in those who have not received cisplatin before.

“If we want to increase the overall survival, we need to also explore new compounds,” Dr. Ray-Coquard said. Drugs targeting the human epidermal growth factor receptor (HER) and angiogenesis have been tested, with lapatinib (Tykerb) and pazopanib (Votrient) found to be too toxic to use in combination but perhaps have an effect on survival when used alone. Cediranib (tentative trade name Recentin) in combination with paclitaxel and cisplatin also improved PFS in a phase II trial.

The best evidence in support of using targeted therapy to date is for bevacizumab. Using bevacizumab in combination with platinum-based combination chemotherapy is supported by the positive findings of the GOG 240 study (N. Engl. J. Med. 2014;370:734-43). This trial tested two hypotheses: first, if a nonplatinum chemotherapy doublet of paclitaxel and topotecan (Hycamtin) would be better than a platinum-based couplet (cisplatin plus paclitaxel); second if receiving additional antiangiogenic therapy with bevacizumab (Avastin) would confer any benefit over these combined chemotherapy regimens.

The results showed that combining topotecan with paclitaxel was not superior to cisplatin plus paclitaxel. When bevacizumab was combined with chemotherapy, however, there were PFS and OS benefits. Bevacizumab conferred an almost 4-month gain in OS, Dr. Ray-Coquard said.

Several factors including age, performance status, and previous treatment and toxicities need to be considered when selecting this or other treatment, she explained in an interview.

Women who have a very poor (≥ 2) performance status or who are symptomatic may not be suitable for the bevacizumab-enhanced therapy, as they may not be able to tolerate the toxicities associated with this regimen.

Notable toxicities reported with the regimen in the GOG 240 study included gastrointestinal fistula and perforation, neutropenia, including febrile neutropenia, hypertension, thrombosis and an increased risk for bleeding in the GI tract.

Understandably, care needs to be taken when considering this regimen for women who may have residual toxicity from other treatments, such as enteritis or cystitis caused by radiotherapy, and those with bowel, bladder, or vaginal involvement.

Women with vaginal bleeding or renal impairment may also not be able to tolerate combined antiangiogenic and chemotherapeutic treatment very well, and women with uncontrolled hypertension might not be good candidates.

Perhaps some of these women could still receive platinum-based chemotherapy without the bevacizumab, but, unfortunately, there will still be women for whom best supportive or palliative care may be the only option, Dr. Ray-Coquard said.

Dr. Ray-Coquard has served on advisory boards convened by Roche and AstraZeneca.