One of the more perplexing issues surrounding scientific questions is the extended time required to provide an answer. Even once a well-considered and vetted conclusion is obtained, an additional interval of time may be required to modify or reverse the answer because of new, relevant data.

A partial explanation for increasingly distressing difficulties with communication between public health officials and the public may be explained by the timelines associated with rigorous scientific investigation, including the conduct and analysis of clinical trials. This was seen especially during the COVID-19 pandemic. Definitive answers to questions relevant to governmental policy to optimize societal health and economic welfare, employer guidance, or individual safety are needed but often what is available in response are no more than reasonable suggestions based on limited and frequently changing data.

The role and benefits of mask mandates or the need for school closures to help ensure public safety in the early days of the pandemic are excellent examples of the dilemma faced by the scientific, medical, and public health communities. In an era of immediate access to information (or in some cases misinformation) provided to society through a variety of social media outlets, the sometimes less than adequate or scientifically supported recommendations/mandates from national or regional scientific and public health officials have not inspired societal confidence.

Further, when questions were raised regarding the safety and effectiveness of the several COVID-19 vaccines, early reassurance had to be based on limited clinical trial data and, admittedly, short follow-up. Critical safety and efficacy features of the products have now been unequivocally documented including observations that specific vaccines appear to possess unique adverse effects. These features would not have been known or available for discussion when the products were initially provided to the public because clinical trials of the agents had not been completed.

A recent report from France has provided data regarding the risk of stroke, pulmonary embolism, or myocardial infarction following review of 46.5 million adults aged 18 to 74 years who received a COVID-19 vaccine between December 27, 2020, and July 20, 2021.

 Although no association was found between these events with mRNA-based vaccination, a potential risk was observed with the administration of an adenoviral-based vaccine product. Again, this information was available only through examination of this large, population-based database after more than 1 year of follow-up.

Similarly, the question of if the risk of developing myocarditis after COVID-19 vaccination vs COVID-19 infection has required time to document in large patient populations. In a recently published report from England, investigators examined individuals who developed myocarditis following adenoviral-based or mRNA-based vaccination or following a positive SARS-CoV-2 test from December 1, 2020, and December 15, 2021.

 The findings revealed that, overall, COVID-19 infection was associated with a greater risk of experiencing this potentially serious cardiac event compared with vaccination.

Another large population-based study from England and Wales examined electronic health records from January to December 2020 to understand the risk of the development of arterial or venous thrombotic disease following the diagnosis of a COVID-19 infection.

 Individuals with confirmed COVID-19 infection had a relatively high risk for experiencing a major arterial or venous thrombotic event that persisted for almost 1 year after diagnosis compared with a noninfected control population.

Other studies that followed the effect of COVID-19 infection or vaccination over time have addressed the risk of psychiatric and neurological complications,

 the potential for the development of chronic fatigue syndrome or myalgic encephalomyelitis in infected children,

In each of the studies patient populations were required to be followed over an extended period to reach clinically meaningful and scientifically (statistically) valid conclusions, including the relative risk of serious adverse effects associated with vaccination. It is also relevant to note that decisions to restrict use of a COVID-19 vaccine product following initial approval have been made based on evolving data.

 This emphasizes how the nature of rigorous regulatory science holds the potential for unanticipated negative outcomes, which can arise despite proper conduct and interpretation of results of clinical trials that led to drug licensing.

Of course, the cancer arena is not immune to the late effects of clinical research efforts that may substantially alter our understanding of both the science and implications for patient treatment. There is no better example of this phenomenon than the recent decision by the FDA and pharmaceutical manufacturers to withdraw prior approval for the use of several commercially available PARP inhibitors as later-line therapy in recurrent epithelial ovarian cancer.

These decisions were based on data generated from several randomized phase 3 trials that suggested a potential negative effect of the drugs on overall survival compared with a cytotoxic drug treatment study control arm. It is interesting to note that until these outcomes were seen, the major concern among clinicians had been for the possible late development of myelodysplastic syndrome or acute leukemia in heavily pretreated patients with ovarian cancer. However, the effects noted in this analysis do not appear to be related to a secondary malignant hematologic process.

These disquieting results were not anticipated and only observed with extended follow-up of the trial population, which again emphasizes how, over time, conclusions of scientifically valid investigative efforts may substantially change.

Maurie Markman, MD, editor in chief, is president of Medicine & Science at Cancer Treatment Centers of America, a part of City of Hope.

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Articles

Time Required to Address Scientific Questions Generates an Information Dilemma

Much has been written regarding the essential role of clinical trials in the major advances in cancer therapy and observed improvement in disease-related morbidity and mortality. The initiation of randomized trials comparing an existing standard of care with a proposed superior strategy has been a vital component in separating hypothesis and hype from objective and reasonably unbiased data.

However, it must be recognized that, to achieve this goal, it is necessary to pay attention to specific and essential compo-nents of the clinical trial process. These include, in the case of randomized studies, the selection of an appropriate control arm and trial sample size. Additionally, investigators should ensure treatment groups are well matched for recognized rele-vant prognostic factors (eg, age, tumor stage, prior therapy, and relevant comorbidities).

Unfortunately, despite great care in the development and conduct of trials in the oncology arena, one additional factor, in the opinion of this commentator, has not received adequate attention. This is the specific investigator (and/or sponsor) interpretation of the actual study results.

Concerns to be noted here may be relatively minor, such as the common use of quite subjective commentary to describe study findings. Examples include terms such as meaning-ful clinical activity with manageable safety, which may fall into this category.1 What is meaningful and manageable to one clinician or patient may not be viewed in this manner by others, especially when the to use such ill-defined and possibly questionable terms in a manuscript submitted for peer review may not be that of the study investigators, but rather come directly from the sponsor or possibly a third-party communications group hired by a pharmaceutical company to provide writing/ editorial assistance. 

What is so difficult about simply concluding that “X% of patients in this study achieved a RECIST-defined response with a median duration of XX months (range, XX-XX),” that “XX% of patients experienced grade 3 or higher adverse effects (AEs), the most common of which were XXXX and XXXX,” or that “X% of patients required hospitalization for treatment-related AEs,” and letting readers decide for them-selves whether the degree of clinical activity was meaningful and toxicity was manageable? 

One may feel greater concern for the interpretation of certain objective data as positive outcomes. For example, in findings published in a recent report, a 7.9% response rate (n = 3 of 38) among patients with cervical cancer whose cancers did not express PD-L1 was suggested to provide a differential between the experimental checkpoint inhibitor being studied and another already on the market.

 Further examination of a larger patient population may confirm the utility of the agent in this clini-cal setting, or the duration of these uncommon responses may be particularly prolonged. However, this commentator feels compelled to ask whether we are now at a point in oncology where an objective response rate of less than 1 in 10 patients following treatment—with what will surely be an expensive anti-neoplastic drug—should be viewed as a positive finding. 

A far more serious concern must be addressed regarding published data that appear to suffer from deficiencies of both scientific and, most disturbingly, basic ethical considerations. Unfortunately, recently reported data from a phase 3 trial exploring a novel anticancer agent in platinum-resistant ovarian cancer provide a disquieting example of this phenomenon.

 What is highlighted for discussion here is not the study design or the experimental agent, but rather the selection of a study control arm—in this instance, the investigator’s choice of single-agent pegylated liposomal doxorubicin (PLD) or topotecan. 

On a scientific basis, the rationale for this decision is quite unclear. It has been unequivocally demonstrated that the combination of single-agent PLD, topotecan, or weekly paclitaxel with bevacizumab (Avastin) significantly improves progression-free survival in platinum-resistant ovarian cancer, leading to FDA approval of this drug strategy.

 The trial highlighted here failed to reveal a statistically significant benefit for the experimental agent compared with the control regimen. However, this raises the question: How would the study results have been interpreted by the study investigators, various regulatory agencies/third-party payers, and, most important, treating oncologists and their patients if the data had revealed statistical superiority of this novel drug vs what is known today to be an inferior treatment approach in this clinical setting?

We now come to the final point; the ethical concern with the control arm in this trial, which called for PLD to be initially administered at a dose of 50 mg/m

. Although initially FDA approved years ago for delivery at this dose level when employed as a single agent in platinum-resistant ovarian cancer, there are extensive data, including results of phase 3 randomized trials in this clinical setting, that reveal the essential therapeutic equivalence of a dose of 40 mg/m2 and substantially reduced well-recognized symptomatic toxicity.

 Further, survey data reveal the drug is rarely administered in platinum-resistant ovarian cancer (4% of patients) in nonresearch, standard-of-care practice.

Therefore, the question to be asked of the study investigators and sponsor is: What was the justification for employing a PLD dose of 50 mg/m2 when this potentially more toxic dose would infrequently be delivered to patients who were not participants in this research? Further, one must ask whether the institutional review boards responsible for ethical oversight of this study were aware of the status of current standard-of-care dosing of PLD, and if not, why not? Did the consent form for this study clearly state that the control arm dose of PLD was higher with the potential for more serious AEs than what the patient would likely receive if they did not participate in this study? Again, if not, why not? 

Although it is not possible to know the thoughts of the peer reviewers and journal editors of this manuscript, it is reasonable to inquire whether they were aware of the concerns highlighted in this commentary.

Much has been written regarding the essential role of clinical trials in the major advances in cancer therapy and observed improvement in disease-related morbidity and mortality. 

Objectively Accurate Interpretation of Clinical Trials Results  Poses a Challenge

It is difficult to dispute that these are troubling times for government officials and public health agencies. Consider the residents of California, who have been facing unprecedented heat and drought. In many regions of the state, officials have asked the public to carefully conserve water and electricity and the potential for wildfires in the coming months is of great concern.

 In addition to environmental factors, in September a rare gubernatorial election will take place in in the state in response to the sitting governor’s actions and decisions during the COVID-19 pandemic.

Further, the rapid spread of the COVID-19 delta variant, currently the most common variant in the United States, has become a concern both at home and abroad.2 How should governments and public health agencies respond? Many officials and individuals appear to believe the pandemic is coming to an end, but objective data challenge this view. For example, in the United Kingdom the delta variant is responsible for at least 90% of all infections and there is worrying evidence that the available COVID-19 vaccines, although effective against the variant, are far less beneficial after the first dose of the required 2-dose regimen. According to current estimates, the delta variant is twice as infectious as the alpha variant, the UK’s previously predominant variant.

The situation in the developing world is far worse.3 A recent report of cases in Africa noted the incidence of 30,000 new cases reported each day, with less than 1% of the population vaccinated. Additionally, the World Health Organization reported that 18 African nations had already used at least 80% of their existing vaccine supplies, with 8 countries reporting that they had no available vaccines.

Public Uncertainty Results in Conflicting Recommendations

Discussions and controversies associated with how the United States (and other countries) can optimally manage future developments associated with the pandemic are continually evolving. Points of contention include efforts addressing the issue of trust associated with COVID-19 vaccination.

 For example, reviewing a survey of more than 6000 individuals conducted in October 2020 and March 2021, at which time there was evidence of the approved acceptance of vaccination through regulatory approvals and mass vaccination programs, investigators concluded that “vaccine hesitancy remained high, especially among young adults and Black and low socioeconomic‒status participants.”

Continued controversy is also associated with the use of masks and social distancing in general societal interactions, the workplace, and schools. The apparent disagreement between the CDC in the United States and declarations emanating from the World Health Organization has likely added a disturbing element of confusion for local and state public health officials who are attempting to make rational recommendations to government leaders.

The list of COVID-19–related scientific concerns does not end here, especially as we learn more about the nature and severity of persistent symptoms lasting longer than 60 days after diagnosis.

 In addition, much remains to be understood regarding the diagnosis and treatment of multisystem inflammatory syndrome in children who receive a COVID-19 diagnosis.

 Just how common is this event and is the apparently rare occurrence a relevant justification for active efforts to vaccinate children?

Finally, although few objectively validated adverse events have been reported, some have been serious and even fatal.

 How should these evolving data influence recommendations for vaccination strategies given how uncommon these events are in the reported real-world experience? Further, how will officials balance multiple pragmatic considerations, including the availability of specific vaccines within a given health care authority?

Mitigating Trust Issues in Scientific Communication

The goal of this commentary is not to resolve these issues but to emphasize the magnitude of the potential concerns to be confronted. Unfortunately, in addition to the issues cited above, one must also consider several increasingly disconcerting events that have been widely reported in the media. These topics call into question the public’s ability to objec-tively trust information from various sources and transcend questions related to vaccine products.

Although space does not permit a thorough discussion of these events, some examples include: questions surrounding the complete unwillingness of China to participate in the critical review process of vaccines; concerns regarding potential conflicts of interest among members of the international scientific community involved in research in this arena

; an objective lack of valid information related to the clinical utility of Chinese COVID-19 vaccines against evolving variants

; and the quite public debate between the manufacturer of one of the mRNA vaccines and the FDA/CDC regarding the need for booster shots.

 There are also the rapidly evolving events and serious implications related to the FDA’s review of potentially inappropriate interactions with a pharmaceutical company in their development of a highly controversial new Alzheimer drug.

This commentary highlights the possibility that such issues could also negatively affect trust in science and public health communi-cation associated with essential efforts in the cancer arena. In this regard, consider the recent report which found that 24% of individu-als who refused to receive, or whose parents refused to consent for, the HPV vaccination in 2019 stated that concerns with “safety and adverse events” were the reason for their decision, despite well-established data that unequivocally refute such fears.

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It is difficult to dispute that these are troubling times for government officials and public health agencies. 

Challenges Arise as Public Health and Scientific Communication Enters Uncharted Territory

The financial impact of a cancer diagnosis on patients and their families is increasingly recognized as a serious and worsening societal concern.

 Costs associated with anticancer therapeutics continue to rise,

 although it also is recognized that the overall effectiveness of therapy has improved.

The relationship between the benefits of care versus the cost of specific interventions (including the administration of pharmaceutical agents) has been a raging debate within the health care community for decades. The urgency associated with the question has only increased in recent years with the rapid acceleration in the development of novel approaches for managing multiple serious medical conditions.

No area of medicine has been more affected than oncology by the striking success of innovation such as new drugs and devices that improve the quantity and quality of life, which essentially has developed in the absence of a coherent strategy to control the rapid rise in the cost of care. This rapid rise has occurred despite the concerted efforts of governmental and private payers and employers. Over the past several years, a number of organizations and academics have advanced their opinions about this societal dilemma. These efforts include attempts to define the “value” of a specific intervention, and, notably, to declare that a particular intervention or drug may not provide sufficient value to justify its use in routine (noninvestigative) oncology care.

This commentary highlights the question of how value in cancer care will be determined in the future and specifically acknowledges the critical difference between the population versus the individual when considering these issues. Samuel Hellman, MD, a noted radiation oncologist and a 2016 Giants of Cancer Care® award winner, eloquently articulated the matter in his provocative 2014 essay published in the Journal of Clinical Oncology

“The utilitarian [approach] is clearly appropriate to public health considerations, but what is learned for public health may not necessarily be in the best interest of an individual patient….Too often we assume that survival or cure is a sufficient metric, with no similar quantitative measure of other factors. This often leads to the so-called best treatment being not what the patient wants. All personal care requires consideration of both the helpful and harmful consequences of treatment in the context of individual patient comorbidity, preferences, and fears.”

This commentary can only begin to scratch the surface of the critical questions posed by Dr Hellman. How much do we really know about the wishes of individuals with cancer and other serious medical conditions regarding their care and their perceptions of meaningful outcomes, as opposed to what clinical investigators, academic leaders, and health policy experts have suggested, or at times proclaimed, in peer-reviewed publications as being the most relevant? Below are several examples to consider.

This degree of discordance between what oncologists claim to have measured and what patients report they actually experienced raises a concern about the reliability of published clinical trial assessments for providing a meaningful assessment at the individual patient level of the risk-to-benefit ratio associated with study regimens.

In a survey of 374 women treated for breast cancer, investigators found that the patients’ perception of the quality of their care was strongly related to the “process of getting care” rather than a measure of the specific medical interventions delivered.

 Therefore, how patients with cancer feel they are being treated by their clinical team may be as important—if not more important—as the regimens they receive.

Several recently reported studies have noted the frequent use in breast cancer (early stage or advanced/metastatic disease) of tumor markers or imaging techniques where there was limited or no evidence that such testing improves clinical outcomes, particularly in individuals at low risk of progression or where there was no evidence of involvement of the organ being examined (eg, central nervous system screening in the absence of neurologic symptoms).

 The studies’ authors high-light the need for future investigation to understand the reasons for widespread use of these strategies. Of note, there is the reassurance “value” that testing may provide a patient when a negative test result is obtained. How does one calculate the emotional versus financial cost benefit associated with such individual reassurance?

The final example relates to the fundamental goals of therapy and the primary outcomes of anticancer drug therapy studies. The industry gold standard is a statistically significant improvement in overall survival in an appropriately powered randomized phase 3 trial. However, in a provocative detailed interview with 22 survivors of ovarian cancer, the respondents challenged this assertion, suggesting instead that “they preferred an individualized approach to care focusing on quality of life.”

Clearly, there is much to learn through a far more expansive exploration of “value,” as defined by the patient with cancer, that hopefully will take place in the future.

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Costs associated with anticancer therapeutics continue to rise, although it also is recognized that the overall effectiveness of therapy has improved.

Patient Perspective Should Be Part of Assessing Value in Cancer Care

Maurie Markman, MD, physician and president of Medicine and Science at Cancer Treatment Centers of America, and editor-in-chief of 

, discusses how privacy and consent in clinical cancer trials have improved over the years.

There has been tremendous change in clinical trials with regard to patient rights, privacy, and autonomy over one's own body and tissues, Markman says. The absolute requirement for consent extends beyond research and into clinical practice, with the exception of emergency scenarios, Markman adds.

Baring lifesaving scenarios, patient consent has grown to become a critical aspect of clinical research, Markman concludes.

Videos

Maurie Markman, MD, discusses how privacy and consent in clinical cancer trials have improved over the years.

Dr. Markman on Privacy and Consent in Clinical Cancer Trials and Beyond

The era of coronavirus disease 2019 has transformed health care in the United States and worldwide, including in the oncology arena. Concerns about the risks associated with spending time in a medical facility for a consultation, test, or procedure have had a substantially negative impact on visits for these services, including well-established cancer screening strategies. The repercussions of delays in diagnosing cancer, either through screening or the presence of early symptoms, and of required modifications in standard-of-care management paradigms are only now beginning to be fully appreciated.

It is not difficult, however, to understand the anxiety that a patient with cancer experiences upon being informed that their treatment will have to be delayed or changed because of the pandemic, as their trusted oncologist struggles to explain the rationale for new therapeutic recommendations and at the same time provide reassurance that the ultimate outcome will not be seriously jeopardized. 

This stress will be added to the potentially serious psychological effects associated with a patient being informed that the diagnosis is 

. Although overall outcomes for cancer treatment have unquestionably improved rather dramatically over the past several decades, the unnerving and frightening words of Susan Sontag in her landmark work “

” remain for many patients (and in a number of clinical settings) as relevant today as when they were written more than 40 years ago: “Someone who has had a coronary is at least as likely to die of another one within a few years as someone with cancer is likely to die soon from cancer. But no one thinks of concealing the truth from a cardiac patient: there is nothing shameful about a heart attack. Cancer patients are lied to, not just because the disease is (or is thought to be) a death sentence but because it is felt to be obscene—in the original meaning of that word: ill-omened, abominable, disgusting, offensive to the senses.”

Much has been written over the past several decades about various approaches that patients, with the assistance of their families, can employ to cope successfully with their cancer journey. One approach that I’ve observed during my 40 years as an oncologist is for the individual to be realistic but remain truly optimistic about the future, regardless of published survival statistics or the often inaccurate focus by many, including the media, on the median in survival curves as the anticipated outcome for an individual patient.

We see reports in high-impact journals where patients with objectively incurable cancers are described as frequently saying that “cure” is their goal, with commentary suggesting that these individuals have either received completely inaccurate data from their oncologists or that they border on the delusional in their beliefs despite being provided with accurate information.

 We even see reports where self-declared experts claim that many patients who are offered entry into early-phase cancer clinical trials suffer from a form of psychological derangement (or, again, have been given inaccurate information) because they quite mistakenly believe they will benefit substantially from study participation; the phenomenon is called 

Much can be said to refute the contention that the current generation of molecularly based early-stage cancer clinical trials lack therapeutic potential, but it is important to note that investigators are likely to miss a fundamental message in patients’ responses to surveys about participation in such studies. Although there will certainly be patients with advanced cancers who fail (or refuse) to understand the facts related to their disease, it is also very possible these individuals fully appreciate their status but still maintain a fervent hope for a favorable outcome, electing to be optimistic rather than pessimistic about their future. 

And what is wrong with this? In fact, existing literature has revealed survival benefits associated with an optimistic perspective following the diagnosis of cancer in certain clinical settings.4 Further, there is evidence that when there is alignment between the treatment goals of patients and their oncologists, substantially less psychological distress is likely to occur.5 

How patients with cancer perceive the potential clinical usefulness of their treatment may also influence specific therapeutic outcomes, as has been shown in studies examining both the placebo (“positive”) and nocebo (“negative”) effects associated with various medications.6 

In summary, it is critical that the oncology community continue to examine the psychological impact of a diagnosis of cancer and its treatment, and learn to optimize approaches that may favorably influence the individual’s cancer journey, including issues of quality of life, emotional well-being, and survival.

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The repercussions of delays in diagnosing cancer, either through screening or the presence of early symptoms, and of required modifications in standard-of-care management paradigms in the COVID-19 era are only now beginning to be fully appreciated. 

Pandemic Heightens Stress of Cancer Diagnosis

The management of carcinoma of the cervix represents a remarkable dichotomy. On the one hand, we have the well-established, truly major public health success associated with population-based screening for the malignancy; more recent, increasingly solid evidence for the actual prevention of the disease as a result of effectively implemented human papillomavirus (HPV) vaccination strategies; and, finally, the documented survival benefits associated with the delivery of a multimodality radiation plus systemic chemotherapy, or chemoradiation, approach in the management of locally advanced disease.

 However, on the other hand, one must now consider the unquestionably objective marginal effectiveness of current therapeutics directed to favorably influence the natural history of recurrent or metastatic cancers.

Today, the medical community possesses diagnostic tools that can detect with great sensitivity and specificity very early-stage invasive disease and pre-cursor abnormalities such as high-grade dysplasia and carcinoma in situ of cervical cancer that, in the large majority of cases, can be effectively managed with the elimination of the potential for tumor progression. Further, vaccination against the HPV types known to be etiologic in causing 70% to 90% of all cervical cancers has the potential to rather dramatically reduce the risks of the development of a cancer responsible for 600,000 new cases and over 300,000 deaths worldwide each year.

Yet, when cervix cancer is detected with documented metastatic disease or the malignancy recurs following definitive local therapy with either surgery or radiotherapy, currently available systemic antineoplastic strategies, unfortunately, remain distressingly limited in their clinical utility.

Systemic Cytotoxic Chemotherapy for Cervical Cancer

Cisplatin has been the cornerstone of the chemotherapeutic management of carcinoma of the cervix for more than 4 decades.

 Over this extended time interval, randomized trials have explored various doses and schedules for delivery of this agent in the malignancy with no evidence for the superiority of a more intensive program in the management of metastatic or recurrent disease than 50 mg/m

 delivered on a schedule of every 3 weeks.

Carboplatin has also been examined for its utility in this clinical setting and, although clearly active, is somewhat less preferred compared with cisplatin due to the frequent prior use of pelvic radiation in disease management. Under these circumstances, carboplatin, being more marrow suppressive than cisplatin, is associated with a greater risk of producing serous bone marrow suppression and subsequent infection.

Cisplatin-based combination chemo-therapy regimens have been extensively explored over the past several decades in the management of metastatic and recurrent disease. Today, the most widely employed combination regimen is likely cisplatin plus paclitaxel, although cisplatin plus topotecan has also been approved by the FDA for use in this clinical setting.

One clinically relevant difficulty associated with determining optimal chemo-therapy in the management of cervical cancer is the established role played by cisplatin-based chemoradiation in the multimodality management of high-risk and locally advanced disease. Several landmark phase 3 randomized trials confirmed the overall survival benefits associated with the concurrent administration of cisplatin and external beam radiation in these difficult clinical set-tings.

 As a result, for a patient who sub-sequently experiences evidence of persistent or recurrent disease following the delivery of cisplatin as a radiosensitizer (eg, 50 mg/m

 per week during external beam radiation), the continued utility of platinum-based chemotherapy remains quite uncertain.

However, as is the well-documented experience in ovarian cancer, limited retrospective data suggest that patients with cervical cancer who previously received cisplatin-based therapy, likely as a component of a chemoradiation regimen and who recur after a reasonably extended period of time, have a reasonable opportunity to experience clinical benefit following reintroduction of this class of agents. In 1 report, patients with a platinum- free interval (PFI) between 12 and 23 and those with PFI greater than 24 months achieved an objective response rate (ORR) of 22% versus 55%, respectively.

In an effort to develop a non–platinum-based systemic chemotherapy program that might be effectively utilized where a patient has previously received cisplatin as a component of a chemoradiation strategy, the National Cancer Institute–affiliated Gynecologic Oncology Group (GOG) directly compared the combination of cisplatin plus paclitaxel to a non–platinum-containing regimen of paclitaxel plus topotecan in metastatic or recurrent carcinoma of the cervix.

 Unfortunately, the results failed to reveal any evidence for the superiority of the non–platinum-containing regimen despite the prior delivery of platinum to this patient population. Further, the 2-drug combination of paclitaxel and topotecan might represent the 2 most “active” nonplatinum cytotoxic agents in the malignancy. No other experience is required to emphasize the magnitude of the limited utility of cytotoxic drugs in cervical cancer.

Although other single agents in this class may be used to provide some degree of palliative relief for individual patients with cervical cancer, the overall efficacy of such a strategy is marginal, with ORRs anticipated to be less than 10%. In addition, tumor regressions in this set-ting are generally of short duration.

It should also be noted that the likelihood of a clinical response being observed in the setting of recurrent or metastatic cervix cancer will be reduced in body regions (eg, pelvis) previously exposed to external beam radiation, likely due to limited blood supply and the presence of a resistant cancer cell population. GOG investigators observed several clinical features that predicted a reduced likelihood of response in an analysis of their experience with platinum-based chemotherapy in addition to previous pelvic radiotherapy. These features included performance status higher than 0, prior treatment with a chemosensitization regimen, time interval from diagnosis to first recurrence of less than 1 year, presence of pelvic disease, and being African American.

Bevacizumab in the Systemic Management of Cervical Cancer

GOG Investigators subsequently examined the efficacy of the antiangiogenic agent, bevacizumab (Avastin), in a group of patients with persistent and recurrent cervical cancer and observed an ORR of 11% (n = 46 patients) with a median duration of response of 6.2 months.

 The toxicity profile of the agent was similar to that observed and anticipated in a relatively heavily pretreated patient population.

These data led to the initiation of a some-what complex randomized trial (NCT00803062) with a 2 × 2 factorial design examining the addition of bevacizumab to a regimen of cisplatin plus paclitaxel or paclitaxel plus topotecan in patients with recurrent, persistent, or metastatic cervical cancer. The addition of bevacizumab led to a statistically significant improvement in median overall survival (17.0 vs 13.3 months, respectively; HR, 0.71; 

The FDA has approved bevacizumab for the treatment of metastatic cervical cancer; however, the addition of the agent to cytotoxic chemotherapy is restricted to a patient population with a reasonably good performance status (

). Further, the adverse effects of bevacizumab, particularly wound healing and the potential for vascular complications, need to be carefully considered for patients undergoing surgery of curative or palliative intent as a component of a multidisciplinary treatment plan.

Immunotherapeutic Approaches in Cervical Cancer Management

The current focus in innovative strategies for the management of advanced cervical cancer is in the domain of immunotherapy. Similar to clinical situations across cancer types, several checkpoint inhibitors have been examined in patients who have recurrent or persistent disease after primary treatment, including cisplatin-based therapies. Evidence of therapeutic benefit, including objective responses (approximately 10%-20%) often of unexpected prolonged duration (> 6 months), has been confirmed.

In addition, a number of novel strategies, including combination checkpoint inhibitors, tumor vaccines, and adoptive T-cell therapies, are under active investigation in the management of recurrent and persistent cervical cancer.

 Investigators anticipate that over the next several years, 1 or more of these approaches will be demonstrated to favorably affect the natural history of this difficult malignancy. 

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The management of carcinoma of the cervix represents a remarkable dichotomy. 

Maurie Markman

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