International Congress on Anti-Cancer Treatment

PARIS – Health status should be evaluated when determining how best to treat an older man with prostate cancer, attendees at an international congress on anticancer treatment were told.

According to recently updated guidelines issued by the International Society of Geriatric Oncology (SIOG), patient preferences should also be a priority when deciding upon prostate cancer treatment, but not their chronological age.

“In the first SIOG guidelines [Crit. Rev. Oncol. Hematol. 2010;731:68-91], we introduced an approach for assessing health status that was somewhat difficult to use by urologists or medical oncologists who had no training in geriatric oncology,” Dr. John-Pierre Droz, professor emeritus of medical oncology at Université Claude Bernard in Lyon, France, said in an interview.

In the updated guidelines (Lancet Oncol. 2014;15:e404-14), however, the use of the G-8 simplified health assessment tool is recommended that takes just 4 minutes to compete and can be used to determine if further health status assessments are necessary.

“This assessment can be performed by a trained nurse,” Dr. Droz said, making the assessment much easier to integrate into clinician’s daily practice.

The G-8 screening tool (Ann. Oncol. 2012;23:2166-72) consists of eight items that take into account patients’ food intake and weight loss in the past 3 months, their body mass index, mobility, prescription drug use, and neuropsychological status. Their age and assessment of their perceived health status in comparison to people of the same age are also included.

A score above 14 is favorable on the G-8 and patients can be categorized as being “fit” and no further geriatric assessment is suggested. But the guidelines recommend a more comprehensive geriatric assessment if a score below this threshold is obtained, which includes comorbidities measured via the Cumulative Illness Rating Scale-Geriatric, evaluation of nutritional status, and patients’ cognitive and physical functions. The latter includes using the familiar concepts of activities of daily living and independent activities of daily living.

Based on these further assessments elderly patients can be categorized as vulnerable, where the health status parameters are potentially improved with appropriate measures; or frail,when changes to health status are deemed permanent or irreversible.

In general, elderly men with prostate cancer who fall into the “fit” health assessment category should have the same treatment options as younger patients. Patients who fall into the “vulnerable” category should be able to receive standard treatment after measures are taken to address any reversible impairments such as malnutrition. Adapted treatment might be more appropriate in senior men who fall into the “frail” category, and palliative care is recommended for those identified with terminal illness.

The potential for side effects to occur and patients’ willingness to accept these is vital to consider when selecting treatments, perhaps more so in elderly individuals who may be more prone to experience adverse events, particularly if they have comorbid disease. Age marginally influences genitourinary and gastrointestinal toxicity seen with external beam radiation therapy, for example, but increases the risk for erectile dysfunction in older men.

Considering first-line treatment for metastatic castrate-resistant prostate cancer disease, “This is exactly the same as in younger patients,” Dr. Droz said. So, docetaxel at the usual dose of 75 mg/m² given three times a week should be suitable for the treatment of both fit and vulnerable patients. A reduced frequency docetaxel regimen, such as weekly or twice weekly, may be more suitable in a frail patient.

Abiraterone acetate is also suitable in the first-line setting in asymptomatic or mildly symptomatic patients who do not have liver metastases. Bone-targeted drugs can also be used to prevent bone loss and for the treatment of bone metastases.

As for second-line treatment, cabazitaxel, abiraterone, and enzalutamide are available, but careful monitoring is needed in older patients, advised Dr. Droz. As in younger men, the optimal sequence of these therapies needs further research.

Dr. Droz commented that the efficacy of treatments for both localized and advanced prostate cancer in older men is similar to that in younger men. However, “the critical issue in the decision-making process is the competition between the risk of death due to prostate cancer and the risk of death due to health status,” he observed.

Dr. Droz has received honoraria from Sanofi.

PARIS – Health status should be evaluated when determining how best to treat an older man with prostate cancer, attendees at an international congress on anticancer treatment were told.

According to recently updated guidelines issued by the International Society of Geriatric Oncology (SIOG), patient preferences should also be a priority when deciding upon prostate cancer treatment, but not their chronological age.

“In the first SIOG guidelines [Crit. Rev. Oncol. Hematol. 2010;731:68-91], we introduced an approach for assessing health status that was somewhat difficult to use by urologists or medical oncologists who had no training in geriatric oncology,” Dr. John-Pierre Droz, professor emeritus of medical oncology at Université Claude Bernard in Lyon, France, said in an interview.

In the updated guidelines (Lancet Oncol. 2014;15:e404-14), however, the use of the G-8 simplified health assessment tool is recommended that takes just 4 minutes to compete and can be used to determine if further health status assessments are necessary.

“This assessment can be performed by a trained nurse,” Dr. Droz said, making the assessment much easier to integrate into clinician’s daily practice.

The G-8 screening tool (Ann. Oncol. 2012;23:2166-72) consists of eight items that take into account patients’ food intake and weight loss in the past 3 months, their body mass index, mobility, prescription drug use, and neuropsychological status. Their age and assessment of their perceived health status in comparison to people of the same age are also included.

A score above 14 is favorable on the G-8 and patients can be categorized as being “fit” and no further geriatric assessment is suggested. But the guidelines recommend a more comprehensive geriatric assessment if a score below this threshold is obtained, which includes comorbidities measured via the Cumulative Illness Rating Scale-Geriatric, evaluation of nutritional status, and patients’ cognitive and physical functions. The latter includes using the familiar concepts of activities of daily living and independent activities of daily living.

Based on these further assessments elderly patients can be categorized as vulnerable, where the health status parameters are potentially improved with appropriate measures; or frail,when changes to health status are deemed permanent or irreversible.

In general, elderly men with prostate cancer who fall into the “fit” health assessment category should have the same treatment options as younger patients. Patients who fall into the “vulnerable” category should be able to receive standard treatment after measures are taken to address any reversible impairments such as malnutrition. Adapted treatment might be more appropriate in senior men who fall into the “frail” category, and palliative care is recommended for those identified with terminal illness.

The potential for side effects to occur and patients’ willingness to accept these is vital to consider when selecting treatments, perhaps more so in elderly individuals who may be more prone to experience adverse events, particularly if they have comorbid disease. Age marginally influences genitourinary and gastrointestinal toxicity seen with external beam radiation therapy, for example, but increases the risk for erectile dysfunction in older men.

Considering first-line treatment for metastatic castrate-resistant prostate cancer disease, “This is exactly the same as in younger patients,” Dr. Droz said. So, docetaxel at the usual dose of 75 mg/m² given three times a week should be suitable for the treatment of both fit and vulnerable patients. A reduced frequency docetaxel regimen, such as weekly or twice weekly, may be more suitable in a frail patient.

Abiraterone acetate is also suitable in the first-line setting in asymptomatic or mildly symptomatic patients who do not have liver metastases. Bone-targeted drugs can also be used to prevent bone loss and for the treatment of bone metastases.

As for second-line treatment, cabazitaxel, abiraterone, and enzalutamide are available, but careful monitoring is needed in older patients, advised Dr. Droz. As in younger men, the optimal sequence of these therapies needs further research.

Dr. Droz commented that the efficacy of treatments for both localized and advanced prostate cancer in older men is similar to that in younger men. However, “the critical issue in the decision-making process is the competition between the risk of death due to prostate cancer and the risk of death due to health status,” he observed.

Dr. Droz has received honoraria from Sanofi.

PARIS – Health status should be evaluated when determining how best to treat an older man with prostate cancer, attendees at an international congress on anticancer treatment were told.

According to recently updated guidelines issued by the International Society of Geriatric Oncology (SIOG), patient preferences should also be a priority when deciding upon prostate cancer treatment, but not their chronological age.

“In the first SIOG guidelines [Crit. Rev. Oncol. Hematol. 2010;731:68-91], we introduced an approach for assessing health status that was somewhat difficult to use by urologists or medical oncologists who had no training in geriatric oncology,” Dr. John-Pierre Droz, professor emeritus of medical oncology at Université Claude Bernard in Lyon, France, said in an interview.

In the updated guidelines (Lancet Oncol. 2014;15:e404-14), however, the use of the G-8 simplified health assessment tool is recommended that takes just 4 minutes to compete and can be used to determine if further health status assessments are necessary.

“This assessment can be performed by a trained nurse,” Dr. Droz said, making the assessment much easier to integrate into clinician’s daily practice.

The G-8 screening tool (Ann. Oncol. 2012;23:2166-72) consists of eight items that take into account patients’ food intake and weight loss in the past 3 months, their body mass index, mobility, prescription drug use, and neuropsychological status. Their age and assessment of their perceived health status in comparison to people of the same age are also included.

A score above 14 is favorable on the G-8 and patients can be categorized as being “fit” and no further geriatric assessment is suggested. But the guidelines recommend a more comprehensive geriatric assessment if a score below this threshold is obtained, which includes comorbidities measured via the Cumulative Illness Rating Scale-Geriatric, evaluation of nutritional status, and patients’ cognitive and physical functions. The latter includes using the familiar concepts of activities of daily living and independent activities of daily living.

Based on these further assessments elderly patients can be categorized as vulnerable, where the health status parameters are potentially improved with appropriate measures; or frail,when changes to health status are deemed permanent or irreversible.

In general, elderly men with prostate cancer who fall into the “fit” health assessment category should have the same treatment options as younger patients. Patients who fall into the “vulnerable” category should be able to receive standard treatment after measures are taken to address any reversible impairments such as malnutrition. Adapted treatment might be more appropriate in senior men who fall into the “frail” category, and palliative care is recommended for those identified with terminal illness.

The potential for side effects to occur and patients’ willingness to accept these is vital to consider when selecting treatments, perhaps more so in elderly individuals who may be more prone to experience adverse events, particularly if they have comorbid disease. Age marginally influences genitourinary and gastrointestinal toxicity seen with external beam radiation therapy, for example, but increases the risk for erectile dysfunction in older men.

Considering first-line treatment for metastatic castrate-resistant prostate cancer disease, “This is exactly the same as in younger patients,” Dr. Droz said. So, docetaxel at the usual dose of 75 mg/m² given three times a week should be suitable for the treatment of both fit and vulnerable patients. A reduced frequency docetaxel regimen, such as weekly or twice weekly, may be more suitable in a frail patient.

Abiraterone acetate is also suitable in the first-line setting in asymptomatic or mildly symptomatic patients who do not have liver metastases. Bone-targeted drugs can also be used to prevent bone loss and for the treatment of bone metastases.

As for second-line treatment, cabazitaxel, abiraterone, and enzalutamide are available, but careful monitoring is needed in older patients, advised Dr. Droz. As in younger men, the optimal sequence of these therapies needs further research.

Dr. Droz commented that the efficacy of treatments for both localized and advanced prostate cancer in older men is similar to that in younger men. However, “the critical issue in the decision-making process is the competition between the risk of death due to prostate cancer and the risk of death due to health status,” he observed.

Dr. Droz has received honoraria from Sanofi.

PARIS – Outcomes for women with progressive or relapsed ovarian carcinoma are significantly improving due to the availability of new molecularly targeted treatments and evolving treatment modalities, medical oncologist Peter Harper said at an international conference on anticancer treatment.

Dr. Harper, who is in private practice in London, said in an interview that the effects of these new approaches were “very significant, such that [clinicians] are now probably doubling the survival, but not doubling the cure rate” in women with advanced disease.

The question for further research, however, is whether using targeted treatments and newer modalities earlier in the course of the disease could make any additional difference to patient outcomes. “As soon as you see a 30%-40% response rate in second-line treatment, when you add that treatment to first-line, you [should also] have a benefit, and that’s happened in all tumor types,” Dr. Harper said.

Around 75% of patients with ovarian cancer will develop recurrent or progressive disease at some point in the course of their disease, he said during his presentation, noting that the disease can be difficult to treat once it has gone past stage I to stage II. Relapse can occur within a few months to a year in patients who do not respond or who are resistant to first-line platinum-based chemotherapy.

But how do you define and know when to treat a patient in relapse? Do you wait until they are symptomatic or do you treat the moment their serum levels of cancer antigen 125 (CA-125) start to rise? Rising CA-125 can be an early signal of relapse, but this is a highly variable time, Dr. Harper said. “Some patients will just have smoldering disease which doesn’t do them any harm for a long time, but for others, there can be a rapid progression.”

Data show that treating patients early in the course of relapse based on their CA-125 levels alone does not influence the outcome. Indeed, similar overall survival (OS) was seen in the OV 05/EORTC 55959 trial (Lancet 2010;376:1155–1163) regardless of whether treatment was initiated early on the basis of rising CA-125 levels or delayed.

Thus treatment should be based on a combination of clinical determinants, symptoms, and radiologic findings, but perhaps not the level of CA-125 on its own, Dr. Harper suggested, and it is important not to forget the psychological burden for patients in knowing their CA-125 result.

Chemotherapy is the standard option for treating platinum-sensitive disease in relapse, with combination therapy generally improving progression-free survival (PFS) and sometimes OS over single-agents, although using combinations can be associated with greater toxicity.

Surgery may be possible Dr. Harper said but “you’ve got to have big eyes.” If there is an obvious obstruction then investigation with a view to surgical removal might be the best course of action.

As for treating platinum-resistant disease or patients with disease that is refractory to first-line therapy, the addition of molecularly targeted agents to chemotherapy is showing great promise.

A host of molecularly targeted drugs have been investigated in the treatment of advanced ovarian carcinoma, including those inhibiting vascular endothelial growth factor (VEGF) or its receptor (VEGFR), and polymerase poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.

The VEGF inhibitor bevacizumab (Avastin) is the most studied, with data from the OCEANS (J. Clin. Oncol. 2012;30:2039-45) and AURELIA (N. Engl. J. Med. 2011;365:2484-96) trials showing that it can increase overall response rates and PFS in both platinum-sensitive and platinum-resistant relapse when added to chemotherapy. No OS benefit was seen in either trial but there was a high (30%-40%) rate of crossover in these trials, and in OCEANS patients received multiple lines of therapy.

“Long postprogression survival means detection of differences in OS is harder and requires a much larger sample size,” Dr. Harper observed. “The reason for stressing this is because we’ve had a lot of trouble with regulators who do not like progression-free survival as an endpoint and want overall survival, and you’re simply not going to see that.”

VEGFR inhibitors evaluated in advanced ovarian cancer in combination with chemotherapy include sorafenib (Nexavar), pazopanib (Votrient), nintedanib (Ofev), and cediranib. Early trial data show these drugs added to chemotherapy can increase PFS in comparison to chemotherapy alone, perhaps even improve OS in the case of cediranib. In the phase II ICON-6 trial, cediranib was added to platinum-based chemotherapy in patients with platinum-sensitive, relapsed disease.

Like bevacizumab, VEGFR-targeting drugs can be associated with a spectrum of side effects, from hypertension to diarrhea, “but you can get quite good at using them and can really minimize side effects”.

Dr. Harper highlighted the potential role of the PARP inhibitor olaparib (Lynparza) as maintenance therapy in patients with platinum-sensitive ovarian cancer. Data from a phase II study (N. Engl. J. Med. 2012:366:1382-92) suggest that it too can improve PFS, with the potential for women to do better if they have the BRCA1 or BRCA2 mutations.

As for immunotherapy, “PD-L1 is very interesting,” Dr. Harper observed. “We know the trials are taking place in ovarian cancer, but it’s much further down the line than in other tumors as ovarian cancer accounts for only 5%-6% of all female cancers, so obviously they’ve tried it in breast cancer and lung cancer first.” Overall, “it’s very hopeful that treatments which are now being used in relapse will be introduced first line and will make a difference,” Dr. Harper said.

PARIS – Outcomes for women with progressive or relapsed ovarian carcinoma are significantly improving due to the availability of new molecularly targeted treatments and evolving treatment modalities, medical oncologist Peter Harper said at an international conference on anticancer treatment.

Dr. Harper, who is in private practice in London, said in an interview that the effects of these new approaches were “very significant, such that [clinicians] are now probably doubling the survival, but not doubling the cure rate” in women with advanced disease.

The question for further research, however, is whether using targeted treatments and newer modalities earlier in the course of the disease could make any additional difference to patient outcomes. “As soon as you see a 30%-40% response rate in second-line treatment, when you add that treatment to first-line, you [should also] have a benefit, and that’s happened in all tumor types,” Dr. Harper said.

Around 75% of patients with ovarian cancer will develop recurrent or progressive disease at some point in the course of their disease, he said during his presentation, noting that the disease can be difficult to treat once it has gone past stage I to stage II. Relapse can occur within a few months to a year in patients who do not respond or who are resistant to first-line platinum-based chemotherapy.

But how do you define and know when to treat a patient in relapse? Do you wait until they are symptomatic or do you treat the moment their serum levels of cancer antigen 125 (CA-125) start to rise? Rising CA-125 can be an early signal of relapse, but this is a highly variable time, Dr. Harper said. “Some patients will just have smoldering disease which doesn’t do them any harm for a long time, but for others, there can be a rapid progression.”

Data show that treating patients early in the course of relapse based on their CA-125 levels alone does not influence the outcome. Indeed, similar overall survival (OS) was seen in the OV 05/EORTC 55959 trial (Lancet 2010;376:1155–1163) regardless of whether treatment was initiated early on the basis of rising CA-125 levels or delayed.

Thus treatment should be based on a combination of clinical determinants, symptoms, and radiologic findings, but perhaps not the level of CA-125 on its own, Dr. Harper suggested, and it is important not to forget the psychological burden for patients in knowing their CA-125 result.

Chemotherapy is the standard option for treating platinum-sensitive disease in relapse, with combination therapy generally improving progression-free survival (PFS) and sometimes OS over single-agents, although using combinations can be associated with greater toxicity.

Surgery may be possible Dr. Harper said but “you’ve got to have big eyes.” If there is an obvious obstruction then investigation with a view to surgical removal might be the best course of action.

As for treating platinum-resistant disease or patients with disease that is refractory to first-line therapy, the addition of molecularly targeted agents to chemotherapy is showing great promise.

A host of molecularly targeted drugs have been investigated in the treatment of advanced ovarian carcinoma, including those inhibiting vascular endothelial growth factor (VEGF) or its receptor (VEGFR), and polymerase poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.

The VEGF inhibitor bevacizumab (Avastin) is the most studied, with data from the OCEANS (J. Clin. Oncol. 2012;30:2039-45) and AURELIA (N. Engl. J. Med. 2011;365:2484-96) trials showing that it can increase overall response rates and PFS in both platinum-sensitive and platinum-resistant relapse when added to chemotherapy. No OS benefit was seen in either trial but there was a high (30%-40%) rate of crossover in these trials, and in OCEANS patients received multiple lines of therapy.

“Long postprogression survival means detection of differences in OS is harder and requires a much larger sample size,” Dr. Harper observed. “The reason for stressing this is because we’ve had a lot of trouble with regulators who do not like progression-free survival as an endpoint and want overall survival, and you’re simply not going to see that.”

VEGFR inhibitors evaluated in advanced ovarian cancer in combination with chemotherapy include sorafenib (Nexavar), pazopanib (Votrient), nintedanib (Ofev), and cediranib. Early trial data show these drugs added to chemotherapy can increase PFS in comparison to chemotherapy alone, perhaps even improve OS in the case of cediranib. In the phase II ICON-6 trial, cediranib was added to platinum-based chemotherapy in patients with platinum-sensitive, relapsed disease.

Like bevacizumab, VEGFR-targeting drugs can be associated with a spectrum of side effects, from hypertension to diarrhea, “but you can get quite good at using them and can really minimize side effects”.

Dr. Harper highlighted the potential role of the PARP inhibitor olaparib (Lynparza) as maintenance therapy in patients with platinum-sensitive ovarian cancer. Data from a phase II study (N. Engl. J. Med. 2012:366:1382-92) suggest that it too can improve PFS, with the potential for women to do better if they have the BRCA1 or BRCA2 mutations.

As for immunotherapy, “PD-L1 is very interesting,” Dr. Harper observed. “We know the trials are taking place in ovarian cancer, but it’s much further down the line than in other tumors as ovarian cancer accounts for only 5%-6% of all female cancers, so obviously they’ve tried it in breast cancer and lung cancer first.” Overall, “it’s very hopeful that treatments which are now being used in relapse will be introduced first line and will make a difference,” Dr. Harper said.

PARIS – Outcomes for women with progressive or relapsed ovarian carcinoma are significantly improving due to the availability of new molecularly targeted treatments and evolving treatment modalities, medical oncologist Peter Harper said at an international conference on anticancer treatment.

Dr. Harper, who is in private practice in London, said in an interview that the effects of these new approaches were “very significant, such that [clinicians] are now probably doubling the survival, but not doubling the cure rate” in women with advanced disease.

The question for further research, however, is whether using targeted treatments and newer modalities earlier in the course of the disease could make any additional difference to patient outcomes. “As soon as you see a 30%-40% response rate in second-line treatment, when you add that treatment to first-line, you [should also] have a benefit, and that’s happened in all tumor types,” Dr. Harper said.

Around 75% of patients with ovarian cancer will develop recurrent or progressive disease at some point in the course of their disease, he said during his presentation, noting that the disease can be difficult to treat once it has gone past stage I to stage II. Relapse can occur within a few months to a year in patients who do not respond or who are resistant to first-line platinum-based chemotherapy.

But how do you define and know when to treat a patient in relapse? Do you wait until they are symptomatic or do you treat the moment their serum levels of cancer antigen 125 (CA-125) start to rise? Rising CA-125 can be an early signal of relapse, but this is a highly variable time, Dr. Harper said. “Some patients will just have smoldering disease which doesn’t do them any harm for a long time, but for others, there can be a rapid progression.”

Data show that treating patients early in the course of relapse based on their CA-125 levels alone does not influence the outcome. Indeed, similar overall survival (OS) was seen in the OV 05/EORTC 55959 trial (Lancet 2010;376:1155–1163) regardless of whether treatment was initiated early on the basis of rising CA-125 levels or delayed.

Thus treatment should be based on a combination of clinical determinants, symptoms, and radiologic findings, but perhaps not the level of CA-125 on its own, Dr. Harper suggested, and it is important not to forget the psychological burden for patients in knowing their CA-125 result.

Chemotherapy is the standard option for treating platinum-sensitive disease in relapse, with combination therapy generally improving progression-free survival (PFS) and sometimes OS over single-agents, although using combinations can be associated with greater toxicity.

Surgery may be possible Dr. Harper said but “you’ve got to have big eyes.” If there is an obvious obstruction then investigation with a view to surgical removal might be the best course of action.

As for treating platinum-resistant disease or patients with disease that is refractory to first-line therapy, the addition of molecularly targeted agents to chemotherapy is showing great promise.

A host of molecularly targeted drugs have been investigated in the treatment of advanced ovarian carcinoma, including those inhibiting vascular endothelial growth factor (VEGF) or its receptor (VEGFR), and polymerase poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.

The VEGF inhibitor bevacizumab (Avastin) is the most studied, with data from the OCEANS (J. Clin. Oncol. 2012;30:2039-45) and AURELIA (N. Engl. J. Med. 2011;365:2484-96) trials showing that it can increase overall response rates and PFS in both platinum-sensitive and platinum-resistant relapse when added to chemotherapy. No OS benefit was seen in either trial but there was a high (30%-40%) rate of crossover in these trials, and in OCEANS patients received multiple lines of therapy.

“Long postprogression survival means detection of differences in OS is harder and requires a much larger sample size,” Dr. Harper observed. “The reason for stressing this is because we’ve had a lot of trouble with regulators who do not like progression-free survival as an endpoint and want overall survival, and you’re simply not going to see that.”

VEGFR inhibitors evaluated in advanced ovarian cancer in combination with chemotherapy include sorafenib (Nexavar), pazopanib (Votrient), nintedanib (Ofev), and cediranib. Early trial data show these drugs added to chemotherapy can increase PFS in comparison to chemotherapy alone, perhaps even improve OS in the case of cediranib. In the phase II ICON-6 trial, cediranib was added to platinum-based chemotherapy in patients with platinum-sensitive, relapsed disease.

Like bevacizumab, VEGFR-targeting drugs can be associated with a spectrum of side effects, from hypertension to diarrhea, “but you can get quite good at using them and can really minimize side effects”.

Dr. Harper highlighted the potential role of the PARP inhibitor olaparib (Lynparza) as maintenance therapy in patients with platinum-sensitive ovarian cancer. Data from a phase II study (N. Engl. J. Med. 2012:366:1382-92) suggest that it too can improve PFS, with the potential for women to do better if they have the BRCA1 or BRCA2 mutations.

As for immunotherapy, “PD-L1 is very interesting,” Dr. Harper observed. “We know the trials are taking place in ovarian cancer, but it’s much further down the line than in other tumors as ovarian cancer accounts for only 5%-6% of all female cancers, so obviously they’ve tried it in breast cancer and lung cancer first.” Overall, “it’s very hopeful that treatments which are now being used in relapse will be introduced first line and will make a difference,” Dr. Harper said.

PARIS – Treatment algorithms for metastatic colorectal cancer are “dynamic and fast changing” in order to keep up with the multiple cytotoxic and biologic options that are currently or will soon be available, Dr. Eric Van Cutsem said at an international congress on anticancer treatment.

“We are making progress. If you look at the past 10-15 years you see that the median survival is going up with the introduction of different agents and with the results of different trials,” Dr. Van Cutsem of University Hospitals Leuven, Belgium, said.

It is becoming increasingly clear that mCRC is “not one disease” and that patient and tumor characteristics vary wildly. Multiple molecular alterations have been identified and there are many molecular signaling pathways known to be involved in tumor progression.

Recent work by the SAGE Colorectal Cancer Subtyping Consortium suggest that there are four or five molecular subtypes of mCRC (Ann. Oncol. 2014;25:iii1-iii9). While it is too early to determine if each subtype might require a different therapeutic strategy, it is another step along the path to achieving the goal of personalized medicine in the disease.

“Treatment choice depends on more than efficacy,” Dr. Van Cutsem said. Together with tumor characteristics (clinical presentation, tumor biology, RAS and BRAF mutation status), patient characteristics (age, performance status, prior adjuvant treatment and comorbidities) and their preferences (expectations, toxicities, socioeconomic factors, and quality of life) need to be incorporated into the treatment plan.

In terms of optimizing the use of targeted treatments in mCRC, Dr. Van Cutsem noted that are three antiangiogenic agents currently approved for use in Europe – bevacizumab (Avastin), aflibercept (Zaltrap), and regorafenib (Stivarga) – and two epidermal growth factor receptor inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix). Promising data from the phase III RAISE trial recently presented at ASCO GI mean that another antiangiogenic agent, ramucirumab (Cyramza), could soon be added to this list.

How to best choose between these agents remains an area of active research but data already show that patients’ RAS status can determine if they might respond to anti-epidermal growth factor receptor monoclonal antibody treatment. BRAF analysis remains more experimental but it can be performed alongside RAS testing with limited extra effort and cost.

Dr. Van Cutsem gave highlights of an expert discussion on mCRC held at the 2014 ESMO/World Congress on Gastrointestinal Cancer in Barcelona, where it was agreed that while chemotherapy remains the backbone of first-line treatment, biologics are also indicated as first-line treatment in most patients, unless there are specific contraindications.

As yet, there is no unequivocal evidence that one biologic agent is superior to another as a first-line choice and the decision to use bevacizumab or an anti-EGFR monoclonal antibody will depend on the subsequent strategy if treatment fails, as well as likely toxicities and patient quality of life.

According to current European Society of Medical Oncology guidelines (Ann. Oncol. 2014;25: iii1–iii9) dividing patients into four categories may help direct the therapeutic strategy. Category 0 patients are those with resectable disease and category 1 patients have potentially resectable disease. Category 2 patients have nonresectable tumors with a heavy tumor load and aggressive biology and Category 3 patients are those who are nonresectable, nonaggressive, and asymptomatic disease.

The categories are not perfect, however, and will be refined in the next iteration of the guidelines due out later this year, Dr. Van Cutsem commented. He added that patients do not always need high-intensity treatment; it depends on what is trying to be achieved. For example, treatment may be more intense at the start when the goal may be to try to shrink tumors to allow surgery and less intense when the aim is to provide good disease control with low toxicity.

In potentially resectable patients in which conversion to surgery is the goal, there is uncertainty on the best combination of cytotoxic and biologic agents to use, with different combinations suggested in RAS mutant and RAS wild-type patients.

In RAS mutant patients, for example, doublet chemotherapy plus bevacizumab or FOLFOXIRI with or without bevacizumab may be reasonable choices, whereas in RAS wild-type patients doublet chemotherapy maybe be combined with an anti-EGFR monoclonal antibody. Another front-line option in the future may be ramucirumab added to FOLFIRI but this has yet to be approved and incorporated into the guidelines. Reevaluation of treatment is important so that patients with resectable disease are not overtreated.

Second-line options may include bevacizumab or aflibercept added to chemotherapy, with third- and later lines of treatment including anti-EGFR monoclonal antibodies possibly used alone in RAS wild-type patients or with irinotecan in the case of cetuximab, and regorafenib in patients who are refractory to other therapies.

Another “new kid on the block” yet to be approved and incorporated into the guidelines is TAS-102, an oral fluoropyrimidine. Data from the recent RECOURSE study (Refractory Colorectal Cancer Study) showed an overall survival benefit of the novel drug vs. placebo when added to best supportive care after two or more prior regimens for mCRC (Ann. Oncol. 2014;25-4: Abstr. LBA13).

Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Lilly, Merck, Merck Serono, Novartis, Roche, and Sanofi.

PARIS – Treatment algorithms for metastatic colorectal cancer are “dynamic and fast changing” in order to keep up with the multiple cytotoxic and biologic options that are currently or will soon be available, Dr. Eric Van Cutsem said at an international congress on anticancer treatment.

“We are making progress. If you look at the past 10-15 years you see that the median survival is going up with the introduction of different agents and with the results of different trials,” Dr. Van Cutsem of University Hospitals Leuven, Belgium, said.

It is becoming increasingly clear that mCRC is “not one disease” and that patient and tumor characteristics vary wildly. Multiple molecular alterations have been identified and there are many molecular signaling pathways known to be involved in tumor progression.

Recent work by the SAGE Colorectal Cancer Subtyping Consortium suggest that there are four or five molecular subtypes of mCRC (Ann. Oncol. 2014;25:iii1-iii9). While it is too early to determine if each subtype might require a different therapeutic strategy, it is another step along the path to achieving the goal of personalized medicine in the disease.

“Treatment choice depends on more than efficacy,” Dr. Van Cutsem said. Together with tumor characteristics (clinical presentation, tumor biology, RAS and BRAF mutation status), patient characteristics (age, performance status, prior adjuvant treatment and comorbidities) and their preferences (expectations, toxicities, socioeconomic factors, and quality of life) need to be incorporated into the treatment plan.

In terms of optimizing the use of targeted treatments in mCRC, Dr. Van Cutsem noted that are three antiangiogenic agents currently approved for use in Europe – bevacizumab (Avastin), aflibercept (Zaltrap), and regorafenib (Stivarga) – and two epidermal growth factor receptor inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix). Promising data from the phase III RAISE trial recently presented at ASCO GI mean that another antiangiogenic agent, ramucirumab (Cyramza), could soon be added to this list.

How to best choose between these agents remains an area of active research but data already show that patients’ RAS status can determine if they might respond to anti-epidermal growth factor receptor monoclonal antibody treatment. BRAF analysis remains more experimental but it can be performed alongside RAS testing with limited extra effort and cost.

Dr. Van Cutsem gave highlights of an expert discussion on mCRC held at the 2014 ESMO/World Congress on Gastrointestinal Cancer in Barcelona, where it was agreed that while chemotherapy remains the backbone of first-line treatment, biologics are also indicated as first-line treatment in most patients, unless there are specific contraindications.

As yet, there is no unequivocal evidence that one biologic agent is superior to another as a first-line choice and the decision to use bevacizumab or an anti-EGFR monoclonal antibody will depend on the subsequent strategy if treatment fails, as well as likely toxicities and patient quality of life.

According to current European Society of Medical Oncology guidelines (Ann. Oncol. 2014;25: iii1–iii9) dividing patients into four categories may help direct the therapeutic strategy. Category 0 patients are those with resectable disease and category 1 patients have potentially resectable disease. Category 2 patients have nonresectable tumors with a heavy tumor load and aggressive biology and Category 3 patients are those who are nonresectable, nonaggressive, and asymptomatic disease.

The categories are not perfect, however, and will be refined in the next iteration of the guidelines due out later this year, Dr. Van Cutsem commented. He added that patients do not always need high-intensity treatment; it depends on what is trying to be achieved. For example, treatment may be more intense at the start when the goal may be to try to shrink tumors to allow surgery and less intense when the aim is to provide good disease control with low toxicity.

In potentially resectable patients in which conversion to surgery is the goal, there is uncertainty on the best combination of cytotoxic and biologic agents to use, with different combinations suggested in RAS mutant and RAS wild-type patients.

In RAS mutant patients, for example, doublet chemotherapy plus bevacizumab or FOLFOXIRI with or without bevacizumab may be reasonable choices, whereas in RAS wild-type patients doublet chemotherapy maybe be combined with an anti-EGFR monoclonal antibody. Another front-line option in the future may be ramucirumab added to FOLFIRI but this has yet to be approved and incorporated into the guidelines. Reevaluation of treatment is important so that patients with resectable disease are not overtreated.

Second-line options may include bevacizumab or aflibercept added to chemotherapy, with third- and later lines of treatment including anti-EGFR monoclonal antibodies possibly used alone in RAS wild-type patients or with irinotecan in the case of cetuximab, and regorafenib in patients who are refractory to other therapies.

Another “new kid on the block” yet to be approved and incorporated into the guidelines is TAS-102, an oral fluoropyrimidine. Data from the recent RECOURSE study (Refractory Colorectal Cancer Study) showed an overall survival benefit of the novel drug vs. placebo when added to best supportive care after two or more prior regimens for mCRC (Ann. Oncol. 2014;25-4: Abstr. LBA13).

Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Lilly, Merck, Merck Serono, Novartis, Roche, and Sanofi.

PARIS – Treatment algorithms for metastatic colorectal cancer are “dynamic and fast changing” in order to keep up with the multiple cytotoxic and biologic options that are currently or will soon be available, Dr. Eric Van Cutsem said at an international congress on anticancer treatment.

“We are making progress. If you look at the past 10-15 years you see that the median survival is going up with the introduction of different agents and with the results of different trials,” Dr. Van Cutsem of University Hospitals Leuven, Belgium, said.

It is becoming increasingly clear that mCRC is “not one disease” and that patient and tumor characteristics vary wildly. Multiple molecular alterations have been identified and there are many molecular signaling pathways known to be involved in tumor progression.

Recent work by the SAGE Colorectal Cancer Subtyping Consortium suggest that there are four or five molecular subtypes of mCRC (Ann. Oncol. 2014;25:iii1-iii9). While it is too early to determine if each subtype might require a different therapeutic strategy, it is another step along the path to achieving the goal of personalized medicine in the disease.

“Treatment choice depends on more than efficacy,” Dr. Van Cutsem said. Together with tumor characteristics (clinical presentation, tumor biology, RAS and BRAF mutation status), patient characteristics (age, performance status, prior adjuvant treatment and comorbidities) and their preferences (expectations, toxicities, socioeconomic factors, and quality of life) need to be incorporated into the treatment plan.

In terms of optimizing the use of targeted treatments in mCRC, Dr. Van Cutsem noted that are three antiangiogenic agents currently approved for use in Europe – bevacizumab (Avastin), aflibercept (Zaltrap), and regorafenib (Stivarga) – and two epidermal growth factor receptor inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix). Promising data from the phase III RAISE trial recently presented at ASCO GI mean that another antiangiogenic agent, ramucirumab (Cyramza), could soon be added to this list.

How to best choose between these agents remains an area of active research but data already show that patients’ RAS status can determine if they might respond to anti-epidermal growth factor receptor monoclonal antibody treatment. BRAF analysis remains more experimental but it can be performed alongside RAS testing with limited extra effort and cost.

Dr. Van Cutsem gave highlights of an expert discussion on mCRC held at the 2014 ESMO/World Congress on Gastrointestinal Cancer in Barcelona, where it was agreed that while chemotherapy remains the backbone of first-line treatment, biologics are also indicated as first-line treatment in most patients, unless there are specific contraindications.

As yet, there is no unequivocal evidence that one biologic agent is superior to another as a first-line choice and the decision to use bevacizumab or an anti-EGFR monoclonal antibody will depend on the subsequent strategy if treatment fails, as well as likely toxicities and patient quality of life.

According to current European Society of Medical Oncology guidelines (Ann. Oncol. 2014;25: iii1–iii9) dividing patients into four categories may help direct the therapeutic strategy. Category 0 patients are those with resectable disease and category 1 patients have potentially resectable disease. Category 2 patients have nonresectable tumors with a heavy tumor load and aggressive biology and Category 3 patients are those who are nonresectable, nonaggressive, and asymptomatic disease.

The categories are not perfect, however, and will be refined in the next iteration of the guidelines due out later this year, Dr. Van Cutsem commented. He added that patients do not always need high-intensity treatment; it depends on what is trying to be achieved. For example, treatment may be more intense at the start when the goal may be to try to shrink tumors to allow surgery and less intense when the aim is to provide good disease control with low toxicity.

In potentially resectable patients in which conversion to surgery is the goal, there is uncertainty on the best combination of cytotoxic and biologic agents to use, with different combinations suggested in RAS mutant and RAS wild-type patients.

In RAS mutant patients, for example, doublet chemotherapy plus bevacizumab or FOLFOXIRI with or without bevacizumab may be reasonable choices, whereas in RAS wild-type patients doublet chemotherapy maybe be combined with an anti-EGFR monoclonal antibody. Another front-line option in the future may be ramucirumab added to FOLFIRI but this has yet to be approved and incorporated into the guidelines. Reevaluation of treatment is important so that patients with resectable disease are not overtreated.

Second-line options may include bevacizumab or aflibercept added to chemotherapy, with third- and later lines of treatment including anti-EGFR monoclonal antibodies possibly used alone in RAS wild-type patients or with irinotecan in the case of cetuximab, and regorafenib in patients who are refractory to other therapies.

Another “new kid on the block” yet to be approved and incorporated into the guidelines is TAS-102, an oral fluoropyrimidine. Data from the recent RECOURSE study (Refractory Colorectal Cancer Study) showed an overall survival benefit of the novel drug vs. placebo when added to best supportive care after two or more prior regimens for mCRC (Ann. Oncol. 2014;25-4: Abstr. LBA13).

Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Lilly, Merck, Merck Serono, Novartis, Roche, and Sanofi.

PARIS – Successful head and neck cancer management can be achieved only if a multidisciplinary approach is taken, experts emphasized at a recent international conference on anticancer treatment.

Because of its very location and complex anatomy, squamous cell cancer of the head and neck (SCCHN) is a difficult tumor to treat, Dr. Jean-Pierre Lefebvre of Centre Oscar Lambret in Lille, France, explained. Two-thirds of tumors are diagnosed at a late stage and often require a combination of therapeutic approaches and thus “combined toxicities.” Patients also frequently have comorbid illnesses that can affect their compliance and tolerance to treatments.

“There is only one solution: a multidisciplinary approach at any time of the management,” Dr. Lefebvre said.

The multidisciplinary approach requires a tight-knit team of imaging specialists; biologists and pathologists; anesthesiologists and surgeons; medical and radiation oncologists; nurses, general practitioners, and other support professions, such as dentists, dietitians, psychologists, speech and physical therapy specialists; and of course, the patients themselves.

Dr. Lefebvre noted that it was vital to provide patients with good information about their disease and its treatment, from the time of diagnosis to explain the various management decisions made by the multidisciplinary team and likely outcomes of the recommended interventions.

The primary goals of treatment are to control disease above the clavicles and to ensure survival, Dr. Lefebvre observed. Other treatment goals include preserving organ function, controlling symptoms, and creating a minimal impact on a patient’s quality of life by providing treatments that offer minimal long-term toxicity, good tolerability, and perhaps most important, good patient satisfaction.

Selecting treatment can be challenging and cannot be done without a multidisciplinary decision. The two main pathways are a surgery-based or radiotherapy-based treatment, but within each there are multiple options and combinations that need careful consideration on a case-by-case basis.

“It’s not a cookbook decision,” agreed Dr. Jan B. Vermorken, emeritus professor of oncology at Antwerp University Hospital, Belgium, who discussed the systemic treatment of head and neck cancer in a separate lecture. He agreed that head and neck cancer treatment is a multidisciplinary challenge that needs to balance the efficacy and tolerability of treatment on an individual basis, and always while considering the patient’s preferences.

“Patients can be very well informed,” Dr. Vermorken noted and suggested that clinicians need to be prepared to help patients understand the information that they find themselves in order to be able to counter any misinformation they might have found.

“There is no treatment without side effects,” Dr. Vermorken stressed. “When there are no side effects, [the treatment] doesn’t work. So you have to warn patients there are always side effects of the treatment they will be given.”

In addition to the importance of the multidisciplinary team in the management of head and neck cancer, understanding the biology of the disease and using systemic treatment are important for treatment, he said. Recent advances in this area include the recognition of the human papillomavirus as a risk factor for and strong predictor of survival in oropharyngeal cancer, and the role of epidermal growth factor receptor to enable targeting with anti-EGFR drugs, such as cetuximab (Erbitux). Systemic treatment for locally advanced disease includes concurrent chemoradiotherapy (CCRT), bioradiotherapy (BRT) with cetuximab and sequential chemotherapy (induction chemotherapy followed by CCRT or BRT).

In most cases of locally advanced SCCHN, the recommended chemotherapy of choice is high-dose cisplatin, given every 3 weeks. Although alternatives to this have been proposed – such as lowering the dose of cisplatin or using carboplatin or cetuximab instead – they have been insufficiently studied and many questions remain unanswered at the moment.

As for the treatment of recurrent or metastatic SCCHN, if it is resectable, then this would be followed by radiotherapy or CCRT. In patients deemed fit enough to handle the regimen, a combination of a platinum agent, 5-fluorouracil (5-FU) and cetuximab) is a new standard first-line regimen, although the role of maintenance cetuximab is unclear.

Better chemotherapy partners for cetuximab or alternatives for anti-EGFR–targeting agents are under investigation. This includes using docetaxel (Taxotere) instead of 5-FU with cetuximab or using lapatinib (Tykerb), afatinib (Gilotrif) or dacomitinib to block multiple human epidermal growth factor receptors or a variety of monoclonal antibodies to try to overcome resistance to anti-EGFR drugs.

Reactivation of immune surveillance by blocking the PD-1 pathway with drugs such as nivolumab (Opdivo) and pembrolizumab (Keytruda) seems to be a promising approach for treating head and neck cancer and is under investigation in other tumors, including non–small cell lung cancer, triple-negative breast cancer, and melanoma, Dr. Vermorken said.Dr. Lefebvre has acted as a consultant to Merck Serono and Sanofi. Dr. Vermorken has participated in advisory boards of AstraZeneca; Boehringer Ingelheim; Debiopharm; Genentech; Merck Serono; Merck, Sharp & Dohme; Oncolytics Biotech; Pierre Fabre; and Vaccinogen; and received lecturer fees from Merck Serono.

PARIS – Successful head and neck cancer management can be achieved only if a multidisciplinary approach is taken, experts emphasized at a recent international conference on anticancer treatment.

Because of its very location and complex anatomy, squamous cell cancer of the head and neck (SCCHN) is a difficult tumor to treat, Dr. Jean-Pierre Lefebvre of Centre Oscar Lambret in Lille, France, explained. Two-thirds of tumors are diagnosed at a late stage and often require a combination of therapeutic approaches and thus “combined toxicities.” Patients also frequently have comorbid illnesses that can affect their compliance and tolerance to treatments.

“There is only one solution: a multidisciplinary approach at any time of the management,” Dr. Lefebvre said.

The multidisciplinary approach requires a tight-knit team of imaging specialists; biologists and pathologists; anesthesiologists and surgeons; medical and radiation oncologists; nurses, general practitioners, and other support professions, such as dentists, dietitians, psychologists, speech and physical therapy specialists; and of course, the patients themselves.

Dr. Lefebvre noted that it was vital to provide patients with good information about their disease and its treatment, from the time of diagnosis to explain the various management decisions made by the multidisciplinary team and likely outcomes of the recommended interventions.

The primary goals of treatment are to control disease above the clavicles and to ensure survival, Dr. Lefebvre observed. Other treatment goals include preserving organ function, controlling symptoms, and creating a minimal impact on a patient’s quality of life by providing treatments that offer minimal long-term toxicity, good tolerability, and perhaps most important, good patient satisfaction.

Selecting treatment can be challenging and cannot be done without a multidisciplinary decision. The two main pathways are a surgery-based or radiotherapy-based treatment, but within each there are multiple options and combinations that need careful consideration on a case-by-case basis.

“It’s not a cookbook decision,” agreed Dr. Jan B. Vermorken, emeritus professor of oncology at Antwerp University Hospital, Belgium, who discussed the systemic treatment of head and neck cancer in a separate lecture. He agreed that head and neck cancer treatment is a multidisciplinary challenge that needs to balance the efficacy and tolerability of treatment on an individual basis, and always while considering the patient’s preferences.

“Patients can be very well informed,” Dr. Vermorken noted and suggested that clinicians need to be prepared to help patients understand the information that they find themselves in order to be able to counter any misinformation they might have found.

“There is no treatment without side effects,” Dr. Vermorken stressed. “When there are no side effects, [the treatment] doesn’t work. So you have to warn patients there are always side effects of the treatment they will be given.”

In addition to the importance of the multidisciplinary team in the management of head and neck cancer, understanding the biology of the disease and using systemic treatment are important for treatment, he said. Recent advances in this area include the recognition of the human papillomavirus as a risk factor for and strong predictor of survival in oropharyngeal cancer, and the role of epidermal growth factor receptor to enable targeting with anti-EGFR drugs, such as cetuximab (Erbitux). Systemic treatment for locally advanced disease includes concurrent chemoradiotherapy (CCRT), bioradiotherapy (BRT) with cetuximab and sequential chemotherapy (induction chemotherapy followed by CCRT or BRT).

In most cases of locally advanced SCCHN, the recommended chemotherapy of choice is high-dose cisplatin, given every 3 weeks. Although alternatives to this have been proposed – such as lowering the dose of cisplatin or using carboplatin or cetuximab instead – they have been insufficiently studied and many questions remain unanswered at the moment.

As for the treatment of recurrent or metastatic SCCHN, if it is resectable, then this would be followed by radiotherapy or CCRT. In patients deemed fit enough to handle the regimen, a combination of a platinum agent, 5-fluorouracil (5-FU) and cetuximab) is a new standard first-line regimen, although the role of maintenance cetuximab is unclear.

Better chemotherapy partners for cetuximab or alternatives for anti-EGFR–targeting agents are under investigation. This includes using docetaxel (Taxotere) instead of 5-FU with cetuximab or using lapatinib (Tykerb), afatinib (Gilotrif) or dacomitinib to block multiple human epidermal growth factor receptors or a variety of monoclonal antibodies to try to overcome resistance to anti-EGFR drugs.

Reactivation of immune surveillance by blocking the PD-1 pathway with drugs such as nivolumab (Opdivo) and pembrolizumab (Keytruda) seems to be a promising approach for treating head and neck cancer and is under investigation in other tumors, including non–small cell lung cancer, triple-negative breast cancer, and melanoma, Dr. Vermorken said.Dr. Lefebvre has acted as a consultant to Merck Serono and Sanofi. Dr. Vermorken has participated in advisory boards of AstraZeneca; Boehringer Ingelheim; Debiopharm; Genentech; Merck Serono; Merck, Sharp & Dohme; Oncolytics Biotech; Pierre Fabre; and Vaccinogen; and received lecturer fees from Merck Serono.

PARIS – Successful head and neck cancer management can be achieved only if a multidisciplinary approach is taken, experts emphasized at a recent international conference on anticancer treatment.

Because of its very location and complex anatomy, squamous cell cancer of the head and neck (SCCHN) is a difficult tumor to treat, Dr. Jean-Pierre Lefebvre of Centre Oscar Lambret in Lille, France, explained. Two-thirds of tumors are diagnosed at a late stage and often require a combination of therapeutic approaches and thus “combined toxicities.” Patients also frequently have comorbid illnesses that can affect their compliance and tolerance to treatments.

“There is only one solution: a multidisciplinary approach at any time of the management,” Dr. Lefebvre said.

The multidisciplinary approach requires a tight-knit team of imaging specialists; biologists and pathologists; anesthesiologists and surgeons; medical and radiation oncologists; nurses, general practitioners, and other support professions, such as dentists, dietitians, psychologists, speech and physical therapy specialists; and of course, the patients themselves.

Dr. Lefebvre noted that it was vital to provide patients with good information about their disease and its treatment, from the time of diagnosis to explain the various management decisions made by the multidisciplinary team and likely outcomes of the recommended interventions.

The primary goals of treatment are to control disease above the clavicles and to ensure survival, Dr. Lefebvre observed. Other treatment goals include preserving organ function, controlling symptoms, and creating a minimal impact on a patient’s quality of life by providing treatments that offer minimal long-term toxicity, good tolerability, and perhaps most important, good patient satisfaction.

Selecting treatment can be challenging and cannot be done without a multidisciplinary decision. The two main pathways are a surgery-based or radiotherapy-based treatment, but within each there are multiple options and combinations that need careful consideration on a case-by-case basis.

“It’s not a cookbook decision,” agreed Dr. Jan B. Vermorken, emeritus professor of oncology at Antwerp University Hospital, Belgium, who discussed the systemic treatment of head and neck cancer in a separate lecture. He agreed that head and neck cancer treatment is a multidisciplinary challenge that needs to balance the efficacy and tolerability of treatment on an individual basis, and always while considering the patient’s preferences.

“Patients can be very well informed,” Dr. Vermorken noted and suggested that clinicians need to be prepared to help patients understand the information that they find themselves in order to be able to counter any misinformation they might have found.

“There is no treatment without side effects,” Dr. Vermorken stressed. “When there are no side effects, [the treatment] doesn’t work. So you have to warn patients there are always side effects of the treatment they will be given.”

In addition to the importance of the multidisciplinary team in the management of head and neck cancer, understanding the biology of the disease and using systemic treatment are important for treatment, he said. Recent advances in this area include the recognition of the human papillomavirus as a risk factor for and strong predictor of survival in oropharyngeal cancer, and the role of epidermal growth factor receptor to enable targeting with anti-EGFR drugs, such as cetuximab (Erbitux). Systemic treatment for locally advanced disease includes concurrent chemoradiotherapy (CCRT), bioradiotherapy (BRT) with cetuximab and sequential chemotherapy (induction chemotherapy followed by CCRT or BRT).

In most cases of locally advanced SCCHN, the recommended chemotherapy of choice is high-dose cisplatin, given every 3 weeks. Although alternatives to this have been proposed – such as lowering the dose of cisplatin or using carboplatin or cetuximab instead – they have been insufficiently studied and many questions remain unanswered at the moment.

As for the treatment of recurrent or metastatic SCCHN, if it is resectable, then this would be followed by radiotherapy or CCRT. In patients deemed fit enough to handle the regimen, a combination of a platinum agent, 5-fluorouracil (5-FU) and cetuximab) is a new standard first-line regimen, although the role of maintenance cetuximab is unclear.

Better chemotherapy partners for cetuximab or alternatives for anti-EGFR–targeting agents are under investigation. This includes using docetaxel (Taxotere) instead of 5-FU with cetuximab or using lapatinib (Tykerb), afatinib (Gilotrif) or dacomitinib to block multiple human epidermal growth factor receptors or a variety of monoclonal antibodies to try to overcome resistance to anti-EGFR drugs.

Reactivation of immune surveillance by blocking the PD-1 pathway with drugs such as nivolumab (Opdivo) and pembrolizumab (Keytruda) seems to be a promising approach for treating head and neck cancer and is under investigation in other tumors, including non–small cell lung cancer, triple-negative breast cancer, and melanoma, Dr. Vermorken said.Dr. Lefebvre has acted as a consultant to Merck Serono and Sanofi. Dr. Vermorken has participated in advisory boards of AstraZeneca; Boehringer Ingelheim; Debiopharm; Genentech; Merck Serono; Merck, Sharp & Dohme; Oncolytics Biotech; Pierre Fabre; and Vaccinogen; and received lecturer fees from Merck Serono.

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.

PARIS – With an expanding array of treatment choices and no fixed algorithm to decide which to use and when, treatment choice for metastatic breast cancer remains based on a conglomeration of tumor biology, prior therapies, toxicities, patients’ performance status and their choice or preference for treatment, Dr. Sandra M. Swain said during a state-of-the-art lecture on metastatic breast cancer at an international congress on anti-cancer treatment.

Compared to 30 years ago when there were only a few drugs available” to treat metastatic disease, “it’s really gratifying to be able to say to a patient, and really mean it, that ‘this is not your last option: we have a lot of other opportunities after this if this treatment doesn’t work or if you don’t like the toxicities from it’,” said Dr. Swain, director of the Washington Cancer Institute at MedStar Washington Hospital Center and professor of medicine at Georgetown University, Washington.

The past decade has seen several drugs approved by the Food and Drug Administration for use in metastatic breast cancer: eribulin in 2010, pertuzumab and everolimus in 2012, trastuzumab-DM1 in 2013, and most recently palbociclib in 2015, she said.

Although treatment goals largely remain the same – to extend survival and minimize toxicity, as well as maximizing patients’ quality of life – there has been a shift to looking at the value of metastatic cancer treatment, taking all these factors and the cost of treatment into consideration.

Looking at available chemotherapies listed in the National Comprehensive Cancer Network guidelines, Dr. Swain noted that no one regimen was preferred over others and highlighted the multiple choices that were recommended.

“My preference is to use sequential single agents, unless we have a patient who is very sick and we need an immediate response, “Dr. Swain said. Response rates are often higher with combination regimens but quality of life may be worse or there are added toxicities that need to be factored into the equation.

Dr. Swain highlighted that newer is not necessarily better. Results of the federal-sponsored CALGB 40502 study, for example, showed that neither weekly nab-paclitaxel (Abraxane) or ixabepilone (Ixempra) was better than weekly treatment with paclitaxel (J. Clin. Oncol. 2012;30:Abstr. CRA1002).

“I think in the U.S. this was very important because paclitaxel is generic and much easier for many patients to afford,” Dr. Swain said.

Expanding Treatment Choices

Studies in metastatic breast cancer highlighted by Dr. Swain include the Triple Negative Trial (TNT), the Breast Cancer Trial of Oral Everolimus 2 (BOLERO-2), and the Tamoxifen Plus Everolimus (TAMRAD) study.

Results of TNT were presented at the 2014 San Antonio Breast Cancer Symposium and showed that carboplatin might be a better choice than docetaxel for women with triple-negative breast cancer and the BRCA1/2 mutation.

BOLERO-2 showed that combining everolimus with exemestane increased progression-free survival by 64% in women with ER-positive, HER2-negative postmenopausal metastatic breast cancer who were refractory to treatment with other AIs (N. Engl. J. Med. 2012;366:520-9). The clinical implications of these data were that the use of everolimus could overcome resistance to endocrine therapy although stomatitis can occur within the first 3 months of treatment. Studies are looking at preventing this side effect with a steroid mouthwash, Dr. Swain said.

TAMRAD was a phase II study looking at the combination of everolimus and tamoxifen, showing improved response rates and overall survival over tamoxifen alone in postmenopausal women with AI-resistant metastatic breast cancer (J. Clin. Oncol. 2012;30:2718-24).

Dr. Swain also discussed the recent fast-tracked FDA approval of palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for use in combination with letrozole (Femara) for estrogen receptor–positive, HER2-negative, postmenopausal, metastatic breast cancer.

Approval was based on the results of the PALOMA-1 study (Lancet Oncol. 2015;16:25-­35), which showed “a striking benefit, with a 50% reduction in progression-free survival” with the combination versus letrozole alone, she said.

“The biggest side effect is neutropenia,” Dr. Swain cautioned, with around 50% of patients treated with the combination experiencing grade 3 or 4 neutropenia.

“So that’s what we need to be careful of now that this drug is going to be on the market,” she said. While there were no reports of febrile neutropenia in the trial, she felt that this would be seen in the “real world” and needs to be considered.

Whether using granulocyte colony–stimulating factor to prevent neutropenia would be possible or even safe is a topic for future research.

Several phase III studies with palbociclib have been completed or are ongoing. These include PALOMA-2 in combination with letrozole as first-line treatment for ER-positive, HER2-negative metastatic breast cancer; PALOMA-3 in combination with fulvestrant (Faslodex) in patients who have progressed on hormonal therapy; PENELOPE-B in the postneoadjuvant setting; and PEARL in women with ER-positive metastatic breast cancer that is not responsive to treatment with an aromatase inhibitor.

There are also two other CDK 4/6 inhibitors currently under investigation: abemaciclib and LEE011, both in phase III trials.

Dr. Swain has received research funding from Genentech, Pfizer, Puma Biotechnology, and Roche. She has also acted as an advisor or consultant and served as a steering committee member for Genentech and Roche, uncompensated. She has received honoraria from Genentech/Roche and Clinigen. She has received travel funding from Genentech.

PARIS – With an expanding array of treatment choices and no fixed algorithm to decide which to use and when, treatment choice for metastatic breast cancer remains based on a conglomeration of tumor biology, prior therapies, toxicities, patients’ performance status and their choice or preference for treatment, Dr. Sandra M. Swain said during a state-of-the-art lecture on metastatic breast cancer at an international congress on anti-cancer treatment.

Compared to 30 years ago when there were only a few drugs available” to treat metastatic disease, “it’s really gratifying to be able to say to a patient, and really mean it, that ‘this is not your last option: we have a lot of other opportunities after this if this treatment doesn’t work or if you don’t like the toxicities from it’,” said Dr. Swain, director of the Washington Cancer Institute at MedStar Washington Hospital Center and professor of medicine at Georgetown University, Washington.

The past decade has seen several drugs approved by the Food and Drug Administration for use in metastatic breast cancer: eribulin in 2010, pertuzumab and everolimus in 2012, trastuzumab-DM1 in 2013, and most recently palbociclib in 2015, she said.

Although treatment goals largely remain the same – to extend survival and minimize toxicity, as well as maximizing patients’ quality of life – there has been a shift to looking at the value of metastatic cancer treatment, taking all these factors and the cost of treatment into consideration.

Looking at available chemotherapies listed in the National Comprehensive Cancer Network guidelines, Dr. Swain noted that no one regimen was preferred over others and highlighted the multiple choices that were recommended.

“My preference is to use sequential single agents, unless we have a patient who is very sick and we need an immediate response, “Dr. Swain said. Response rates are often higher with combination regimens but quality of life may be worse or there are added toxicities that need to be factored into the equation.

Dr. Swain highlighted that newer is not necessarily better. Results of the federal-sponsored CALGB 40502 study, for example, showed that neither weekly nab-paclitaxel (Abraxane) or ixabepilone (Ixempra) was better than weekly treatment with paclitaxel (J. Clin. Oncol. 2012;30:Abstr. CRA1002).

“I think in the U.S. this was very important because paclitaxel is generic and much easier for many patients to afford,” Dr. Swain said.

Expanding Treatment Choices

Studies in metastatic breast cancer highlighted by Dr. Swain include the Triple Negative Trial (TNT), the Breast Cancer Trial of Oral Everolimus 2 (BOLERO-2), and the Tamoxifen Plus Everolimus (TAMRAD) study.

Results of TNT were presented at the 2014 San Antonio Breast Cancer Symposium and showed that carboplatin might be a better choice than docetaxel for women with triple-negative breast cancer and the BRCA1/2 mutation.

BOLERO-2 showed that combining everolimus with exemestane increased progression-free survival by 64% in women with ER-positive, HER2-negative postmenopausal metastatic breast cancer who were refractory to treatment with other AIs (N. Engl. J. Med. 2012;366:520-9). The clinical implications of these data were that the use of everolimus could overcome resistance to endocrine therapy although stomatitis can occur within the first 3 months of treatment. Studies are looking at preventing this side effect with a steroid mouthwash, Dr. Swain said.

TAMRAD was a phase II study looking at the combination of everolimus and tamoxifen, showing improved response rates and overall survival over tamoxifen alone in postmenopausal women with AI-resistant metastatic breast cancer (J. Clin. Oncol. 2012;30:2718-24).

Dr. Swain also discussed the recent fast-tracked FDA approval of palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for use in combination with letrozole (Femara) for estrogen receptor–positive, HER2-negative, postmenopausal, metastatic breast cancer.

Approval was based on the results of the PALOMA-1 study (Lancet Oncol. 2015;16:25-­35), which showed “a striking benefit, with a 50% reduction in progression-free survival” with the combination versus letrozole alone, she said.

“The biggest side effect is neutropenia,” Dr. Swain cautioned, with around 50% of patients treated with the combination experiencing grade 3 or 4 neutropenia.

“So that’s what we need to be careful of now that this drug is going to be on the market,” she said. While there were no reports of febrile neutropenia in the trial, she felt that this would be seen in the “real world” and needs to be considered.

Whether using granulocyte colony–stimulating factor to prevent neutropenia would be possible or even safe is a topic for future research.

Several phase III studies with palbociclib have been completed or are ongoing. These include PALOMA-2 in combination with letrozole as first-line treatment for ER-positive, HER2-negative metastatic breast cancer; PALOMA-3 in combination with fulvestrant (Faslodex) in patients who have progressed on hormonal therapy; PENELOPE-B in the postneoadjuvant setting; and PEARL in women with ER-positive metastatic breast cancer that is not responsive to treatment with an aromatase inhibitor.

There are also two other CDK 4/6 inhibitors currently under investigation: abemaciclib and LEE011, both in phase III trials.

Dr. Swain has received research funding from Genentech, Pfizer, Puma Biotechnology, and Roche. She has also acted as an advisor or consultant and served as a steering committee member for Genentech and Roche, uncompensated. She has received honoraria from Genentech/Roche and Clinigen. She has received travel funding from Genentech.

PARIS – With an expanding array of treatment choices and no fixed algorithm to decide which to use and when, treatment choice for metastatic breast cancer remains based on a conglomeration of tumor biology, prior therapies, toxicities, patients’ performance status and their choice or preference for treatment, Dr. Sandra M. Swain said during a state-of-the-art lecture on metastatic breast cancer at an international congress on anti-cancer treatment.

Compared to 30 years ago when there were only a few drugs available” to treat metastatic disease, “it’s really gratifying to be able to say to a patient, and really mean it, that ‘this is not your last option: we have a lot of other opportunities after this if this treatment doesn’t work or if you don’t like the toxicities from it’,” said Dr. Swain, director of the Washington Cancer Institute at MedStar Washington Hospital Center and professor of medicine at Georgetown University, Washington.

The past decade has seen several drugs approved by the Food and Drug Administration for use in metastatic breast cancer: eribulin in 2010, pertuzumab and everolimus in 2012, trastuzumab-DM1 in 2013, and most recently palbociclib in 2015, she said.

Although treatment goals largely remain the same – to extend survival and minimize toxicity, as well as maximizing patients’ quality of life – there has been a shift to looking at the value of metastatic cancer treatment, taking all these factors and the cost of treatment into consideration.

Looking at available chemotherapies listed in the National Comprehensive Cancer Network guidelines, Dr. Swain noted that no one regimen was preferred over others and highlighted the multiple choices that were recommended.

“My preference is to use sequential single agents, unless we have a patient who is very sick and we need an immediate response, “Dr. Swain said. Response rates are often higher with combination regimens but quality of life may be worse or there are added toxicities that need to be factored into the equation.

Dr. Swain highlighted that newer is not necessarily better. Results of the federal-sponsored CALGB 40502 study, for example, showed that neither weekly nab-paclitaxel (Abraxane) or ixabepilone (Ixempra) was better than weekly treatment with paclitaxel (J. Clin. Oncol. 2012;30:Abstr. CRA1002).

“I think in the U.S. this was very important because paclitaxel is generic and much easier for many patients to afford,” Dr. Swain said.

Expanding Treatment Choices

Studies in metastatic breast cancer highlighted by Dr. Swain include the Triple Negative Trial (TNT), the Breast Cancer Trial of Oral Everolimus 2 (BOLERO-2), and the Tamoxifen Plus Everolimus (TAMRAD) study.

Results of TNT were presented at the 2014 San Antonio Breast Cancer Symposium and showed that carboplatin might be a better choice than docetaxel for women with triple-negative breast cancer and the BRCA1/2 mutation.

BOLERO-2 showed that combining everolimus with exemestane increased progression-free survival by 64% in women with ER-positive, HER2-negative postmenopausal metastatic breast cancer who were refractory to treatment with other AIs (N. Engl. J. Med. 2012;366:520-9). The clinical implications of these data were that the use of everolimus could overcome resistance to endocrine therapy although stomatitis can occur within the first 3 months of treatment. Studies are looking at preventing this side effect with a steroid mouthwash, Dr. Swain said.

TAMRAD was a phase II study looking at the combination of everolimus and tamoxifen, showing improved response rates and overall survival over tamoxifen alone in postmenopausal women with AI-resistant metastatic breast cancer (J. Clin. Oncol. 2012;30:2718-24).

Dr. Swain also discussed the recent fast-tracked FDA approval of palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for use in combination with letrozole (Femara) for estrogen receptor–positive, HER2-negative, postmenopausal, metastatic breast cancer.

Approval was based on the results of the PALOMA-1 study (Lancet Oncol. 2015;16:25-­35), which showed “a striking benefit, with a 50% reduction in progression-free survival” with the combination versus letrozole alone, she said.

“The biggest side effect is neutropenia,” Dr. Swain cautioned, with around 50% of patients treated with the combination experiencing grade 3 or 4 neutropenia.

“So that’s what we need to be careful of now that this drug is going to be on the market,” she said. While there were no reports of febrile neutropenia in the trial, she felt that this would be seen in the “real world” and needs to be considered.

Whether using granulocyte colony–stimulating factor to prevent neutropenia would be possible or even safe is a topic for future research.

Several phase III studies with palbociclib have been completed or are ongoing. These include PALOMA-2 in combination with letrozole as first-line treatment for ER-positive, HER2-negative metastatic breast cancer; PALOMA-3 in combination with fulvestrant (Faslodex) in patients who have progressed on hormonal therapy; PENELOPE-B in the postneoadjuvant setting; and PEARL in women with ER-positive metastatic breast cancer that is not responsive to treatment with an aromatase inhibitor.

There are also two other CDK 4/6 inhibitors currently under investigation: abemaciclib and LEE011, both in phase III trials.

Dr. Swain has received research funding from Genentech, Pfizer, Puma Biotechnology, and Roche. She has also acted as an advisor or consultant and served as a steering committee member for Genentech and Roche, uncompensated. She has received honoraria from Genentech/Roche and Clinigen. She has received travel funding from Genentech.

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.