CANCER TREATMENT DURING PREGNANCY

Because cancer during pregnancy is a rare occurrence, with an incidence ranging from 0.02% to 0.10%, there is a scarcity of research to guide women and their physicians on treatment. Now, some experts have offered reassurance that it is possible to appropriately treat the mother without terminating the pregnancy.

Pregnancy should be preserved whenever possible with breast and gynecologic cancers, according to 2 separate review articles published in the February 11 issue of the Lancet. The most common malignancies diagnosed during pregnancy are gynecological (primarily uterine or cervical, and less frequently ovarian) and breast cancers; pregnancy does not have a deleterious effect on the prognosis of either.

Although prognosis and treatment success depends on the individual patient, it is possible to provide standard therapy to the mother while safeguarding the fetus.

Decisions about treatment for cancer in a pregnant woman can be difficult because of the conflict between the wellbeing of the mother and that of her unborn child, note Philippe Morice, MD, from the Institut Gustave Roussy, Villejuif, France, and colleagues in a comment accompanying the review papers.

They point out that the physician must define "when and how far to push back usual treatment limits to satisfy the patient's [ethical, legal, and/or personal beliefs]," but also must provide accurate information and consider the oncologic risks.

"The main goal is to offer pregnant patients the same optimum management (and therefore similar predicted survival) as nonpregnant patients," they write. Therefore, physicians must clearly define the real oncologic risk for each patient. Physicians need to stop thinking about cancer and pregnancy in general; instead, they need to focus on the particular cancer and its known characteristics.

Except for leukemia, true oncologic emergencies in pregnant women are rare, Dr. Morice and colleagues point out. This is fortunate because "time is required to deliberate and to draw up a personalized treatment plan that the patient will view as clear and balanced."

Treating cancer during pregnancy is still associated with unacceptable outcomes, such as the termination of pregnancies and the choice of an inadequate strategy for treatment of a tumor, they write.

"The treatment of every pregnant woman, and by extension every woman of childbearing age, should include a wider reflection on how to preserve the pregnancy or subsequent fertility, or both," Dr. Morice and colleagues explain. "Preservation of fertility in young women with cancer (an entirely new specialty, oncofertility) is every patient's right."

Pregnancy During Breast Cancer

In the review article on breast cancer during pregnancy, Frédéric Amant, MD, from the Multidisciplinary Breast Cancer Center, Leuven Cancer Institute, Katholieke Universiteit Leuven, Belgium, and colleagues note that a multidisciplinary focus and a cautious approach to radiotherapy are needed. A diagnostic strategy designed to reduce the burden of fetal radiation exposure needs to be established in a multidisciplinary setting.

Terminating the pregnancy does not improve the breast cancer prognosis, explained Dr. Amant. "We believe that fear of the toxic effects of chemotherapy should not be a reason for termination of pregnancy, and fear should not be a reason to delay maternal treatment or to induce prematurity," he told Medscape Medical News.

The therapeutic strategy should also be discussed within a multidisciplinary setting, and should adhere as closely as possible to standard protocols for nonpregnant women, say the authors, but fetal safety must also be considered.

Dr. Amant added that sometimes oncologists underestimate the long-term consequences of prematurity. "We believe children suffer more from prematurity than from antenatal exposure to chemotherapy," he said.

Until now, it was "easy to terminate pregnancy because the long-term effects were not known," said Dr. Amant. "With the current data, I believe it becomes unethical to terminate pregnancy when cancer is diagnosed."

A study recently published by Dr. Amant and colleagues showed that fetal exposure to chemotherapy was not associated with increased central nervous system, cardiac, or auditory morbidity. In addition, exposure did not appear to be associated with impairments to general health or growth, and cognitive development was age-adequate.

He added that if this trend is confirmed in more children with a longer follow-up, "I believe termination will be more difficult to defend."

In their review paper, Dr. Amant and colleagues explain that surgery, chemotherapy, and radiotherapy for breast cancer are possible during pregnancy, with the caveat that treatment should be tailored to the individual patient.

Generally, surgery can be conducted safely during any stage of pregnancy and most anesthetic agents seem to be safe for the fetus, they point out. The choice of surgery should follow the same guidelines as those for nonpregnant women, and radiation therapy after a breast-conservation procedure is rarely a concern; most women receive chemotherapy and delay radiotherapy until after delivery.

After the first trimester of pregnancy, chemotherapy can be either adjuvant or neoadjuvant, and the decision to use chemotherapy should follow the same guidelines as for nonpregnant women, the authors report. The goal should also be a term delivery (37 weeks or more), and premature birth should be avoided if possible.

Cervical and Ovarian Cancers During Pregnancy

In the review paper on gynecologic cancers, Dr. Morice and his colleagues from France and the United States focused on the 2 most common and complex gynecologic cancers — cervical and ovarian. As in breast cancer, a multidisciplinary discussion is essential for optimal disease management, note the authors. Physicians need to consider the possibility of saving the fetus and the effect of therapy on the woman's reproductive capacity.

Dr. Morice and colleagues point out that until the 1980s, cervical cancer diagnosed during the first 2 trimesters was managed by ending the pregnancy and radically treating the cervical neoplasm. The current trend is to try to preserve the pregnancy, especially in patients with early-stage disease with no nodal involvement.

The management of cervical cancer depends largely on 4 criteria: the extent of local spread, nodal status, pregnancy trimester, and histologic subtype. The authors explain that in early-stage cervical cancer, during the first and at the beginning of the second trimester, magnetic resonance imaging and laparoscopic lymphadenectomy can be used to help plan a conservative approach.

Among women with small tumors and without nodal spread, postponing treatment until fetal maturity and delivery can be discussed. In these cases, radical trachelectomy and neoadjuvant chemotherapy might be appropriate.

The treatment of patients with locally advanced disease is controversial — neoadjuvant chemotherapy with preservation of the pregnancy or chemotherapy and radiotherapy — and needs to be discussed on a case-by-case basis. Tumor size, radiologic findings, the term of pregnancy, and the patient's wishes must be taken into consideration, the authors note.

The management of ovarian cancer is dependent on histologic type, stage, and pregnancy trimester. In patients with peritoneal spread or high-risk early-stage disease, preservation of the pregnancy might be possible with neoadjuvant chemotherapy, according to Dr. Morice and colleagues.

Chemotherapy is generally necessary to achieve a cure in ovarian cancer, and the risk for a congenital malformation or miscarriage as a consequence is very high during the first trimester. In such cases, "consideration of a therapeutic abortion versus delayed treatment should be discussed with the patient," they write. However, treatment during subsequent trimesters can be given according to the usual standard chemotherapy guidelines for both germ-cell tumors and epithelial ovarian cancer; in most cases, there are generally no irreversible consequences for the fetus.

It is also usually not necessary to induce premature delivery if the cancer is controlled with chemotherapy.

"Clinical studies are needed, particularly for key issues in clinical management, such as an intentional delay in early-stage cervical cancer or radical trachelectomy and neoadjuvant chemotherapy, to establish the balance between the best chance of cure for the patient and preservation of a healthy fetus," Dr. Morice and colleagues emphasize.

Nefertiti duPont, MD, MPH, who was approached by Medscape Medical News for an independent comment, noted that this is "an excellent review of a difficult topic."

"When diagnosed early, gynecologic cancers in pregnancy can lead to good outcomes for the mother and infant," said Dr. duPont, who is assistant professor and director of the High Risk Ovarian Cancer Screening Clinic, Roswell Park Cancer Institute, Buffalo, New York. "The most important issues are close follow-up of the mother during her pregnancy and postpartum course, and long-term follow-up of the infant."

What is also critical is a multidisciplinary team to ensure that the mother and baby have the best possible outcomes, she explained.

Several areas in the review, however, could be strengthened, Dr. duPont noted. "Clinicians should provide psychosocial and emotional support to the mother during diagnosis and treatment," she said. "Also, most studies recommend postponing chemotherapy within 3 weeks of delivery to avoid neonatal myelosuppression."

MULTIDRUG RESISTANT TB IS SPREADING

Cases of multidrug-resistant tuberculosis (MDR-TB) hit an all-time high worldwide in 2009 and 2010, with 1 country reporting multidrug resistance in 65.1% of all previously treated TB cases, according to the latest World Health Organization (WHO) study, published in the February Bulletin of the World Health Organization.

Matteo Zignol, MD, MPH, from the Stop TB Department, WHO, Geneva, Switzerland, and colleagues analyzed data collected from 2007 to 2010 from 80 countries and 8 territories. The analysis showed that Eastern Europe and central Asia continue to record the world's highest proportion of MDR-TB. Still, there are no data on drug-resistant TB from much of Russia, India, and Africa, and from large portions of Eastern Europe and central Asia, the authors report.

"Surveillance of resistance to drugs is the cornerstone of TB control," Dr. Zignol said in a news release. "Following 15 years of intensive effort, we now have high quality data for two-thirds of countries in the world. At the same time, we don't know the full extent of the problem because we lack data from many countries, in particular India and most of Africa where the TB burden is high."

One bright spot in new surveillance efforts, the authors points out, is China, which conducted its first nationwide survey in 2007. Dr. Zignol and colleagues call China's efforts "a critical step towards addressing MDR-TB in one of the largest TB control programmes in the world." China, India, and Russia are home to more than half of the world's MDR-TB cases, the report states.

Worldwide, 3.4% (95% confidence interval [CI], 1.9% - 5.0%) of all new TB cases are multidrug-resistant, meaning Mycobacterium tuberculosis resists treatment with at least rifampicin and isoniazid. Among previously treated TB cases worldwide, 19.8% (95% CI, 14.4% - 25.1%) of TB cases are multidrug resistant, according to the report.

Some MDR-TB cases are considered extensively drug resistant (XDR), meaning they not only meet the criteria for multidrug resistance but also fail to respond adequately to fluoroquinolone and at least 1 second-line injectable agent, such as amikacin, kanamycin, or capreomycin. Worldwide, some 9.4% (95% CI, 7.4% - 11.6%) of MDR-TB cases are XDR cases. The number of MDR-TB cases considered to be XDR cases rose to more than 10% in South Africa (10.5%) and 3 former Soviet Union countries: Estonia (19.7%), Latvia (15.1%), and Tajikistan (Dushanbe city and Rudaki district, 21.0%).

However, only 38 countries and 3 territories reported surveillance data for XDR-TB. Among those, only 6 had more than 10 cases of XDR.

The Russian oblast of Murmansk, on the Kola Peninsula near Finland, had the highest level of newly diagnosed MDR-TB, at 28.9%. The Republic of Moldova, a landlocked country between Ukraine and Romania, had the highest rate of MDR-TB among previously treated TB cases, at 65.1%.

TB cases resistant to several treatment regimens require longer and more treatment regimens and are less likely to be cured. Despite the rising number of resistant cases, in 2010, only 16% of the world's patients with MDR-TB received appropriate treatment, the WHO report reveals.

In the United States, MDR-TB cases are in decline, falling even more quickly than new TB cases, the authors report. US TB cases have dropped 5.1% per year since 1996, and MDR-TB diagnoses declined 5.4% per year in the same period. Surveillance showed that 1.1% of new TB cases diagnosed in the United States were multidrug resistant in 2010, and 4.4% of previously treated cases were multidrug resistant.

Despite high MDR-TB rates in Latvia and Estonia, both those countries, along with the United States, have seen a decline in new TB cases and in MDR-TB cases during the last decade.

MDR-TB is increasing most rapidly in Botswana, at 10.9% per year; Peru, at 19.4% per year; and the Republic of Korea, with an increase of 4.3% per year. The Republic of Korea is also recording a 7.4% annual increase in new TB cases. Despite increases in MDR-TB rates, Botswana's overall new case rate is nearly stable, increasing at 0.3% per year, and Peru's rate of new cases is declining by 3.3% per year.

WHO began gathering drug resistance data from 127 countries in 1994 with the launch of the Global Project on Anti-tuberculosis Drug Resistance Surveillance. Today, 64 countries have continuous surveillance based on routine susceptibly testing of all patients with TB. The rest of the countries rely on special surveys of representative patient samples.

Among the report's other findings:

• Countries with new cases of MDR-TB at more than 12% include Belarus, at 25.7%; Estonia, at 18.3%; several oblasts of the Russian Federation, with Murmansk having the highest at 28.9%; and Tajikistan, with Dushanbe city and Rudaki district at 16.5%.
• Countries with MDR-TB in previously treated cases above 50% included Belarus, at 60.2%; Lithuania, at 51.5%; the Republic of Moldova, at 65.1%, 5 oblasts of the Russian Federation; and Tajikistan (Dushanbe city and Rudaki district), at 61.6%.
• Patients with TB who have HIV were no more likely to have a drug-resistant form of TB than those without HIV. In the 17 countries and 1 territory that looked at HIV status, odds of having MDR-TB among HIV-positive cases was 40% higher than among those without HIV (pooled odds ratio [OR], 1.4; 95% CI, 0.7 - 3.0; OR consistent across countries, I² = 23.2%; P = .19), but the difference was not significant.
• The sex of the patients with TB was not a factor in resistance. Among the 58 countries and 2 special territories that collected data on the sex of patients with MDR-TB, odds of MDR-TB were 10% higher among women (OR, 1.1; 95% CI, 0.8 - 1.4; OR heterogeneous across countries, I² = 32.9%; P = .009), which is not statistically significant.

PET-CT HAS PREDICTIVE VALUE AFTER RADIOCHEMOTHERAPY FOR HEAD AND NECK CANCERS

Oncologists at St. John Hospital in Grosse Pointe Woods, Michigan, routinely perform a surveillance positron emission tomography (PET)/computed tomography (CT) scan 6 to 9 weeks after the definitive chemoradiation treatment of patients with squamous cell carcinoma of the head and neck — even when a recurrence is not clinically suspected.
And these clinicians will continue to do so in light of the results from a small study conducted at their center, despite the "controversy" surrounding such routine follow-up, said study author Yasir Rudha, MD, MBChB, a radiation oncologist at the hospital.
"We will keep doing it because of the high negative predictive value," said Dr. Rudha during a press conference at the 2012 Multidisciplinary Head and Neck Cancer Symposium. He was referring to the fact that, in their study, about half of the patients with no clinical evidence of recurrence had a subsequent negative surveillance scan and that all of them remained free of locoregional recurrence on further follow-up.
"Almost all of those patients will be able to avoid neck dissection," predicted David Raben, MD, from the University of Colorado in Aurora, about patients with negative surveillance scans. He was moderator of the press conference. In the past, most of these patients would have automatically gone on to a neck dissection as part of treatment, he said.
The surveillance scans had another benefit — they identified patients with disease recurrence that preceded any clinical manifestation of recurrence. The rate for finding these "true positives" was 53%, Dr. Rudha reported. However, this benefit was somewhat offset by the "high false-positive rate" of 46%, he admitted.
"The routine use of PET/CT scanning in the follow-up of patients with squamous cell carcinoma of the head and neck may be useful for the detection of locoregional recurrences before they become clinically apparent," he summarized.
Study Results and Controversies
Dr. Rudha and colleagues identified 234 patients with head and neck cancer at their center who were treated with chemoradiation and then underwent a posttherapy PET/CT scan from 2006 to 2010.
A retrospective chart review was performed for 45 of those cases, all of whom had a "clinical no-evidence-of-disease " status at the time of the surveillance PET/CT scan.
Of these 45 patients, 30 had a negative PET/CT scan, and all 30 remained free from locoregional relapse at the time of last follow-up. However, the median time of follow-up for the 30 patients was not presented by Dr. Rudha.
The scans identified 15 patients with abnormalities requiring further evaluation. Biopsy showed malignancies in 8 of the 15 patients (53%). (Six of the 8 showed occult persistent disease at the primary site.)
The other 7 cases of abnormalities turned out to be false positives (46%). Thus, patients underwent "unnecessary work-up and/or biopsy evaluation," he said. "Caution should be shown when ordering biopsies after abnormal scans to prevent excessive unnecessary biopsies," he added.
However, overall, the study results provide "support for the routine use of PET scanning as a surveillance method following treatment of head and neck cancer," Dr. Rudha summarized.
Dr. Rudha suggested that this is an uncommon finding in the literature.
He acknowledged that, in most studies, PET scans are performed only when recurrent disease is clinically suspected. "Only a few publications report the value of PET examination at a fixed time after the end of treatment," he told reporters at the press conference.
Dr. Raben endorsed using PET after treatment. The scans are "absolutely critical" for the monitoring and follow-up of these patients. But he added that the use of PET scans in head and neck cancer "continues to evolve."

10% RATE OF ORAL HPV INFECTION

A major study of oral infection with human papillomavirus (HPV) — now known to cause of a subset of oropharyngeal cancer — has found a much higher incidence in men than in women and has established sexual transmission as the main way it spreads. It also raises questions about whether existing HPV vaccines offer protection.
There is a rising incidence in oral HPV infection and in HPV-positive oropharyngeal cancer in the United States. "The curves are a little bit frightening," said lead author Maura Gillison, MD, PhD, from Ohio State University in Columbus. But she pointed out that vaccines against HPV are already marketed, so "we have the means to prevent this already sitting on our pharmacy shelves."
The HPV vaccines (Gardasil and Cervarix) were developed to offer protection against cervical cancer after the link between cervical HPV infection and cervical cancer was firmly established, and are targeted mainly to girls.
The link between oral HPV infection and oral HPV cancer was established more recently; Dr. Gillison reported that the research is about 20 years behind that for cervical cancer. There is speculation — although no hard data — that the same vaccines could offer protection against HPV-associated oral cancer. Because this is more prevalent in men, it would make sense to vaccinate boys as well as girls.
"We need to have thorough and accurate discussions about HPV vaccination," Dr. Gillison said. "We have identified a new cancer...and we have identified its Achilles heel," she added.
Dr. Gillison spoke at a presscast at the 2012 Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Therapeutic and Radiation Oncology and held in Phoenix, Arizona. The study was published online January 26 in JAMA: The Journal of the American Medical Association to coincide with its presentation.
Sexual Transmission
This the first major prevalence study of oral HPV infection in the United States, according to anaccompanying editorial, subtitled "Hazard of Intimacy."
Editorialist Hans Schlecht, MD, MMSc, from Drexel University College of Medicine in Philadelphia, Pennsylvania, writes that the "results are remarkable for a number of reasons," including the fact that they allow estimation of oral HPV prevalence based on sexual experience, smoking status, and immune suppression.
One of the main findings from this study is that the main method of transmission is sexual, and that the prevalence of oral HPV infection increases with the number of sexual partners reported.
Another finding is "a striking bimodal pattern with age" in men, with peaks in men 30 to 34 and 60 to 64 years of age.
During the presscast, Dr. Gillison speculated that these peaks in oral HPV infection might be partially explained by a "birth cohort" effect. The peak in older men could be related to the fact that they would have been making their sexual debut during the sexual revolution of the 1960s; the dip in middle-aged men could be the result of the dampening impact that the HIV epidemic had on sexual behavior. The peak in younger men could be related to one result of that epidemic — the perception that oral sex is "safe sex."
The new data showing a rising incidence of HPV oropharyngeal cancer raise questions about exactly how safe oral sex is.
In his editorial, Dr. Schlecht suggests that "clinicians should encourage their patients who engage in oral sex to use barrier protection."
First Major Prevalence Study
This study used 2009/10 data from the National Health and Nutrition Examination Survey (NHANES), and analyzed tissue collected from an oral rinse and gargle collected from 5579 people 14 to 69 years of age.
The overall prevalence of HPV oral infection was 6.9%; the particular strain associated with oropharyngeal cancer, HPV16, was found in 1%. "Although this 1% may sound small, this means that around 2.1 million individuals in the United States are infected," Dr. Gillison explained.
However, the incidence in men is significantly higher than it is in women (10.0% vs 3.6%; P < .001).
In addition, the bimodal distribution, with peaks in younger and older individuals, was seen only in men. Why the incidence of oral HPV infection in men is so much higher is not clear, Dr. Gillison said.
Men did report having more sexual partners than women, but this difference in sexual behavior explains only about 16% of the difference in prevalence, the authors note. Another explanation could be higher rate of transmission to men performing oral sex on woman than to women performing oral sex on men; there is some evidence for this in the data. But there are also many other factors, including the fact that women who have already been exposed to cervical HPV infection have greater protection against subsequent oral HPV infection.
The bimodal distribution of oral HPV infection in men is different than that of cervical HPV infection, which peaks in women in their 20s and then generally drops off, although a later peak in older women is seen in some populations.
"It is clear that the natural history of HPV is different in the 2 genders," Dr. Gillison reported.
There was a higher prevalence of oral HPV infection in black than in white people, although this did not reach statistical significance (10.5% vs 6.5%; P = .06). There was also a higher prevalence in current smokers and heavy consumers of alcohol (which increased with intensity of use for both), as well as in current and former marijuana users.
There was little HPV oral infection in individuals who had no history of any sexual contact. Compared with this group, the prevalence was 8 times higher in sexually experienced individuals, and increased significantly with the number of sexual partners. For instance, the prevalence was 20% in people who reported having more than 20 sexual partners.
"These data indicate that transmission by casual, nonsexual contact is likely to be unusual," the authors write.
They note that previous studies have suggested a link between oral sexual behavior and an increased risk for HPV-positive oropharyngeal cancer, but the way the data were collected in the current study precluded association with any particular behavior. However, the data did show that oral HPV infection is more common in sexually experienced people who do not report performing oral sex than in those who were not sexually experienced, which suggests that transmission occurs through other sexually associated contact, such as deep kissing.
This adds weight to the notion that HPV vaccination should be targeted at individuals who are 9 to 13 years of age, in an effort to reach them before any sexual behavior, including deep kissing, begins. This suggestion has been made previously by Dr. Gillison, although she emphasized that protection against oral HPV infection with the existing HPV vaccines has not been proven. She has been trying to conduct such a study for the past 5 years, but has run into funding problems; she hopes to hear soon about funding from the National Cancer Institute, she told journalists in the audience.
Extending HPV vaccination to offer protection against oropharyngeal cancer was discussed by several experts, in addition to Dr. Gillison, last year when it was highlighted by the American Society for Clinical Oncology.
The study was supported by an unrestricted grant from Merck, and was also funded by Ohio University and the Intramural Research Program of the National Cancer Institute. Dr. Gillison reports acting as a consultant to Merck and GlaxoSmithKline, both manufacturers of HPV vaccines. Dr. Schlecht has disclosed no relevant financial relationships.