Lewis et al comprehensively review current epidemiologic, clinical, prognostic, and treatment considerations for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC).[1] As they discuss, the incidence of HPV-OPSCC has increased rapidly over the past several decades in the United States and will soon exceed the incidence of cervical cancer.[2] They state that “the emergence of HPV-OPSCC has been deemed an epidemic of our time.”[1] The designation of HPV-OPSCC as an “epidemic” has numerous important implications, several of which will be discussed in this commentary.

First, the rising incidence combined with the favorable prognosis of HPV-OPSCC implies that the population of HPV-OPSCC survivors is expanding. Therefore, there is an increasing need to understand and address the survivorship considerations that are unique to this population. For example, treatment-related toxicities can greatly affect health-related quality of life (HRQOL); thus, in a population in which the majority of patients will survive for more than 5 years,[2] long-term toxicities emerge as a significant concern. As a result, multiple deintensification trials for HPV-OPSCC treatment are currently underway. In addition, there is preliminary evidence that HRQOL trajectories for HPV-OPSCC patients are distinct from those of their HPV-negative counterparts, with greater declines in HRQOL during the diagnosis and treatment period[3]; further study will be necessary to clarify trends and determinants of HRQOL for these patients. Finally, unlike other head and neck cancers, HPV-OPSCC results from a sexually transmitted infection. The impact of this reality on patients’ psychosocial well-being, including their relationships, has not been well explored.[4]

Second, the current deficits in effective screening for HPV-OPSCC and its early detection will take on increasing importance as projected incidence trends are realized. Higher incidence of disease improves the clinical utility and cost-effectiveness of screening programs, thus underscoring the importance of identifying high-risk populations. Screening for OPSCC is not yet feasible for a number of reasons, including a lack of identifiable premalignant lesions amenable to an oropharyngeal “Pap test equivalent,”[5] the lack of highly sensitive oral and serum markers of HPV-OPSCC, and the relatively low incidence of HPV-OPSCC in the general population. However, the distinct epidemiology of HPV-OPSCC may allow for identification of high-risk groups, likely based on sex, smoking history, and sexual history, in whom screening would be appropriate and cost-effective.[6]

Third, an essential component of managing any epidemic is the development of effective prevention, eg, vaccines. Vaccines against high-risk types of HPV were initially targeted toward cervical disease and have been shown to have efficacy in the prevention of cervical premalignancy and malignancy.[7,8] HPV 16, which causes over 90% of HPV-OPSCCs, is included in bivalent, quadrivalent, and now nine-valent vaccines. Preliminary evidence suggests that these vaccines are effective in preventing oral HPV infection, the presumptive precursor to HPV-OPSCC.[9] However, no prospective clinical trials have been reported, and there are numerous questions regarding the ability of the HPV vaccines to alter the forecasted epidemic of HPV-OPSCC.

The natural history of HPV infection in the oral cavity and oropharynx appears to differ from that of cervical infection. For example, the peak prevalence of cervical HPV infection is shortly after sexual debut, whereas oral HPV infection prevalence is bimodal, with peaks in early and later adulthood.[10,11] Even if vaccination prevents oral HPV infection around the time of sexual debut, it is unknown whether this protection will endure to later adulthood.

Another consideration is the relative contribution of the local compared with the systemic immune response to oral HPV infection; the oral cavity and oropharynx (sampled by oral secretions) are a unique immunologic milieu, and oral tolerance to foreign antigens is well described.[12,13] Whether the systemic and cervical immunity provided by vaccination will extend to the oral cavity is unclear. Therefore, while there is optimism that the vaccine will reduce the future burden of HPV-OPSCCs, there is a significant knowledge gap.

Whether or not the vaccine proves efficacious in preventing HPV-OPSCCs, it unequivocally prevents other HPV-related cancers. Thus, the low compliance with vaccine recommendations in the United States presents a major public health challenge and opportunity. Although vaccination has been recommended since 2006 for 11- to 12-year-old girls, with catch-up vaccination to age 26, and since 2011 for 11- to 12-year-old boys, with catch-up vaccination to age 21,[14] the uptake of HPV vaccination in the United States remains remarkably low. In 2013, among 13- to 17-year-olds in the United States, just 57% of females and 35% of males received at least one dose of the three-dose series, and only 38% of females and 14% of males received all three doses.[15] The most common reasons cited by parents for not vaccinating their children were a lack of knowledge, healthcare provider’s failure to recommend the vaccine, and a belief that the vaccine was not needed or necessary.[16]

Even though discussing the prevention of cancers caused by a sexually transmitted infection in the context of preadolescents may be uncomfortable, increasing vaccination coverage is currently the most promising option for reversing the HPV-OPSCC epidemic, while also preventing a host of anogenital cancers. Indeed, the President’s Cancer Panel Annual Report recently identified HPV vaccination as a national priority, stating that “such a significant opportunity to prevent cancers in the US and around the world is rare.”[17]

Finally, we must not forget the role of tobacco in head and neck cancers, including HPV-OPSCC. Tobacco continues to cause the majority of head and neck cancers, and although patients with HPV-OPSCC are less likely to smoke than those with HPV-negative head and neck cancer, many still report a history of tobacco use.[18-22] Tobacco smoking independently worsens the prognosis of HPV-OPSCCs in a dose-dependent fashion.[18,23] Consequently, many of the deintensification trials summarized by Lewis et al incorporate pack-years of smoking into eligibility criteria. Tobacco smoking also appears to have a role in the early pathogenesis of HPV-OPSCC, in that it independently increases the risk of oral HPV infection,[10,24] as well as the likelihood that these infections will persist.[25] Clearly, tobacco plays a major role in HPV-OPSCC, and we must continue to emphasize tobacco prevention and cessation efforts in the context of head and neck cancer care.

In summary, there is an epidemic of HPV-OPSCC in the United States, which has widespread implications and highlights existing knowledge gaps. There is a need for increased emphasis on understanding survivorship considerations for the growing population of patients with HPV-OPSCC. Although screening methods for HPV-OPSCC have not yet been developed, population-based prevention may be achievable through HPV vaccination, but only if concerted efforts are made to increase vaccine uptake in the United States. Finally, tobacco smoking prevention and cessation must remain at the forefront of the HPV-OPSCC discussion.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

. Lewis A, Kang R, Levine A, Maghami E. The new face of head and neck cancer: the HPV epidemic. Oncology (Williston Park). 2015;29:616-26.

 Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294-301.

 Sharma A, Mendez E, Yueh B, et al. Human papillomavirus-positive oral cavity and oropharyngeal cancer patients do not have better quality-of-life trajectories. Otolaryngol Head Neck Surg. 2012;146:739-45.

 Rettig E, Kiess AP, Fakhry C. The role of sexual behavior in head and neck cancer: implications for prevention and therapy. Expert Rev Anticancer Ther. 2015;15:35-49.

 Fakhry C, Rosenthal BT, Clark DP, Gillison ML. Associations between oral HPV16 infection and cytopathology: evaluation of an oropharyngeal “pap-test equivalent” in high-risk populations. Cancer Prev Res (Phila). 2011;4:1378-84.

 Gillison ML, Chaturvedi A, Anderson WF, Fakhry C. The epidemiology of HPV-positive head and neck squamous cell carcinoma. J Clin Oncol. 2015. In press.

 Centers for Disease Control and Prevention. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2010;59:626-9.

 Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372:711-23.

 Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013;8:e68329.

 Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307:693-703.

 Markowitz LE, Sternberg M, Dunne EF, et al. Seroprevalence of human papillomavirus types 6, 11, 16, and 18 in the United States: National Health and Nutrition Examination Survey 2003-2004. J Infect Dis. 2009;200:1059-67.

 Pabst O, Mowat AM. Oral tolerance to food protein. Mucosal Immunol. 2012;5:232-9.

 Fakhry C, Marks MA, Gilman RH, et al. Comparison of the immune microenvironment of the oral cavity and cervix in healthy women. Cytokine. 2013;64:597-604.

 Petrosky E, Bocchini JA, Jr, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2015;64:300-4.

 Elam-Evans LD, Yankey D, Jeyarajah J, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years––United States, 2013. MMWR Morb Mortal Wkly Rep. 2014;63:625-33.

 Stokley S, Jeyarajah J, Yankey D, et al. Human papillomavirus vaccination coverage among adolescents, 2007-2013, and postlicensure vaccine safety monitoring, 2006-2014––United States. MMWR Morb Mortal Wkly Rep. 2014;63:620-4.

 Accelerating HPV vaccine uptake: urgency for action to prevent cancer. A report to the President of the United States from the President’s Cancer Panel. Bethesda, MD: National Cancer Institute; 2014.

 Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35.

 Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100:407-20.

 Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261-9.

 Hafkamp HC, Manni JJ, Haesevoets A, et al. Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. Int J Cancer. 2008;122:2656-64.

 D’Souza G, Gross ND, Pai SI, et al. Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol. 2014;32:2408-15.

 Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol. 2012;30:2102-11.

 Fakhry C, Gillison ML, D’Souza G. Tobacco use and oral HPV-16 infection. JAMA. 2014;312:1465-7.

 Beachler DC, Sugar EA, Margolick JB, et al. Risk factors for acquisition and clearance of oral human papillomavirus infection among HIV-infected and HIV-uninfected adults. Am J Epidemiol. 2015;181:40-53.

Articles

Although screening methods for HPV-OPSCC have not yet been developed, population-based prevention may be achievable through HPV vaccination, but only if concerted efforts are made to increase vaccine uptake in the United States.

Implications of the New Face of Head and Neck Cancer

The last decade has seen a dramatic increase in the use of neoadjuvant systemic therapy in the management of breast cancer; over this period, our understanding of its potential benefits has shifted. The initial rationale for neoadjuvant therapy-to address micrometastatic disease early in the management course-has not proven fruitful, with randomized studies demonstrating no survival differences based on chemotherapy sequencing.[1,2] The neoadjuvant approach was typically reserved, therefore, for those with locally advanced disease, with the aim of converting inoperable disease to operable, or for patients who would otherwise be candidates for mastectomy but desired breast conservation. In addition, the preoperative approach serves as a platform for novel drug development, with pathologic complete response (pCR) serving as a surrogate for clinical outcomes. Moreover, because pCR has been observed to correlate with lower risk of locoregional recurrence (LRR),[3] pCR also has the potential to influence adjuvant radiation treatment, including decisions regarding omitting radiation or reducing the radiation target volume in selected cases.

The review article by Chapman and Jagsi expertly summarizes the evidence supporting use of postmastectomy radiotherapy (PMRT) in patients with node-positive breast cancer.[4] It describes the data, albeit limited, regarding the impact of neoadjuvant therapy on outcomes and patient selection for PMRT, including data supporting the omission of PMRT in selected patients with pCR.[4] Several issues raised in this review merit special attention.

The large National Surgical Adjuvant Breast and Bowel Project (NSABP) studies B-18 and B-27, designed to evaluate the impact of chemotherapy sequencing on survival outcomes, have also demonstrated that response to neoadjuvant chemotherapy is predictive of LRR.[1] However, as discussed in Chapman and Jagsi’s review, this relationship differs with breast cancer subtype. There is considerable variation in the response to chemotherapy, with rates of pCR lower than 10% in patients with estrogen receptor (ER)/progesterone receptor(PR)-positive, human epidermal growth factor 2 (HER2)-negative disease and as high as 60% in those with triple-negative or HER2-positive disease.[5-7] In those subtypes with a high rate of pCR, achieving this endpoint is highly correlated with locoregional outcomes. The Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) analysis described in the review demonstrates this well, with an LRR rate after mastectomy of 6.2% for patients with triple-negative disease and pCR, compared with 22.1% in patients with triple-negative disease without pCR.[8] However, those subtypes that generally have a lower rate of response to neoadjuvant therapy-the ER/PR-positive and HER2-negative tumors-also have lower rates of LRR with or without pCR. Recent data from the Memorial Sloan Kettering Cancer Center similarly showed a risk of LRR of 26% in patients with triple-negative disease without a pCR but a rate of only 4% in those with hormone receptor–positive disease without pCR.[7] In addition, disease-free survival after LRR is higher in patients with ER-positive disease than in those with triple-negative disease.[9] Thus, lack of response to therapy may not be an equally strong predictor of outcomes in all patients. Moreover, the use of pCR to tailor PMRT decisions in ER/PR-positive disease may lead to its overuse in these lower-risk patients.

Another important issue is how the timing and extent of nodal surgery should impact treatment decisions. The practice of upfront sentinel lymph node biopsy (SLNB) prior to neoadjuvant treatment has the advantage of providing accurate pathologic nodal assessment for staging at diagnosis but precludes the ability to assess nodal response to treatment and subsequent tailoring of treatment on this basis. Ultrasound-guided biopsy of abnormal axillary nodes has a lower sensitivity than SLNB but still detects involved lymph nodes in over 50% of cases; this is an alternative approach to axillary staging before neoadjuvant chemotherapy.[10] This approach allows SLNB after chemotherapy, with the benefit of assessing response to treatment and avoiding axillary dissection in those who become node-negative.[11] Increasing evidence suggests that when both dye and radiotracer are used and two or more sentinel nodes are identified, the false-negative rate of SLNB after neoadjuvant chemotherapy for patients who initially had node-positive disease is similar to that of upfront SLNB.[12] It is likely that accurate staging postchemotherapy is a more meaningful predictor of LRR than accurate staging prechemotherapy. Ideally, a limited axillary assessment postchemotherapy will provide accurate information and at the same time minimize treatment morbidity and allow for tailoring of adjuvant radiation decisions.

In light of the increased use of both neoadjuvant therapy and mastectomy in breast cancer patients, the ability to appropriately select patients for PMRT after neoadjuvant treatment is increasingly important and poses one of the greatest challenges in breast radiation oncology at this time. The ongoing studies described in the review article, NSABP B-51/Radiation Therapy Oncology Group 1304 and Alliance 011202, are well designed to answer many of the important questions, but, as Chapman and Jagsi point out, questions will remain unanswered regarding the optimal extent of nodal radiation. There may also be insufficient power to fully understand the impact of subtype on outcomes. Future study is needed to determine whether molecular markers or other measures of response, beyond pCR, can be used to tailor treatment decisions, especially for patients with subtypes less likely to develop pCR. In addition, trials evaluating escalation of therapy in patients with residual triple-negative disease are needed.

Current data challenge the statement that recommendations for PMRT should be based on the highest clinical or pathologic stage. Instead, data suggest that in a majority of patients, the pathologic stage after neoadjuvant chemotherapy carries more prognostic value. Over-radiation remains a substantial problem in management of patients after mastectomy. Although a meta-analysis demonstrated a survival advantage with PMRT even in patients with one positive lymph node,[13] more recent studies demonstrate substantially lower rates of LRR,[12] probably related to the beneficial impact of modern systemic therapy. Response to systemic therapy may prove to be a powerful tool for selecting patients with node-positive disease at diagnosis who can ultimately avoid radiotherapy. The ongoing cooperative group studies are poised to provide further support for the tailoring of adjuvant radiation decisions based on response to treatment rather than solely on the upfront clinical stage. Ultimately, the ability to limit local therapy in node-positive patients may be one of the greatest advantages of preoperative treatment.

 Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project protocols B-18 and B-27. J Clin Oncol. 2008;26:778-85.

 Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;30:96-102.

 Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol. 2012;30:3960-6.

 Chapman CH, Jagsi R. Postmastectomy radiotherapy after neoadjuvant chemotherapy: a review of the evidence. Oncology (Williston Park). 2015;29:657-66.

Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.

 von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796-804.

 Yang TJ, Morrow M, Modi S, et al. The effect of molecular subtype and residual disease on locoregional recurrence in breast cancer patients treated with neoadjuvant chemotherapy and postmastectomy radiation. Ann Surg Oncol. 2015 July 1. [Epub ahead of print]

 Mamounas EP, Cortazar P, Zhang L, et al. Locoregional recurrence (LRR) after neoadjuvant chemotherapy (NAC): pooled-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). J Clin Oncol. 2014;32(suppl 26):abstr 61.

 Braunstein LZ, Niemierko A, Shenouda MN, et al. Outcome following local-regional recurrence in women with early-stage breast cancer: impact of biologic subtype. Breast J. 2015;21:161-7.

Feng Y, Huang R, He Y, et al. Efficacy of physical examination, ultrasound, and ultrasound combined with fine-needle aspiration for axilla staging of primary breast cancer. Breast Cancer Res Treat. 2015;149:761-5.

 Mamounas EP. Impact of neoadjuvant chemotherapy on locoregional surgical treatment of breast cancer. Ann Surg Oncol. 2015;22:1425-33.

 Boughey JC, Suman VJ, Mittendorf EA, et al. Factors affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast cancer patients enrolled in ACOSOG Z1071 (Alliance). Ann Surg. 2015;261:547-52.

McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383:2127-35.

Current data challenge the statement that recommendations for postmastectomy radiotherapy should be based on the highest clinical or pathologic stage. Instead, data suggest that in a majority of patients, the pathologic stage after neoadjuvant chemotherapy carries more prognostic value. 

Should Response to Preoperative Therapy Guide Local Management in Node-Positive Breast Cancer?

As technology has affected every segment of society, we in the oncology community have a responsibility to make every effort to utilize these advances to enable the broadest possible outreach to our patient population in a continual process of quality improvement. In their excellent review, Dr. Charlton and colleagues[1] have reminded us of the special challenges that rural patients face regarding healthcare in general and oncology specifically, and of potential applications of advanced technology to improve the quality of both the physician and patient experiences.

As the national shortage of oncologists becomes more apparent over the next decade, the existing gulf in services between urban and rural patients will increase exponentially. Beginning with the basics of access to cancer care, 20% of the US population resides in rural areas, but only 3% of medical oncologists practice there. Two Iowa studies[2,3] documented an average one-way travel time of about 1 hour for chemotherapy and 90 minutes for radiotherapy for rural patients. This has resulted in patients making therapeutic choices based on employment and transportation issues rather than on health issues alone. A clear example of this is the increased frequency of mastectomy over breast conservation in rural communities.[4]

Rural patients also have more limited health insurance coverage than their urban counterparts. A striking observation is that nearly two-thirds of the rural uninsured who could have been covered by the Affordable Care Act (ACA) are living in states that are not expanding Medicaid, so they are not able to benefit from the health insurance exchanges.[5] This places an additional burden on rural oncologists in traditional fee-for-service private practices who may not be integrated into organized hospital-based healthcare delivery systems. It is much easier for an oncologist to limit a private practice based on insurance status in an urban setting where alternate providers exist than in a rural setting where there is no one else that the patient can see.

Rural patients also deal with diminished availability of a comprehensive set of psychosocial support networks, including palliative and hospice care. Financial support remains at the root of this problem.

Charlton et al carefully identified multiple strategies to address these issues, including outreach clinics, teleoncology systems, virtual tumor boards, and workforce initiatives. All of these methods are of value and should be considered and adapted to local and regional realities.

When creating our Tahoe Forest Cancer Program in Lake Tahoe, California, we had the advantage of having no legacy oncology services for a rural catchment area of 50,000 people. The closest city with cancer services was Reno, Nevada (45–90 minutes away), and the closest university cancer center was the University of California, Davis (UC Davis; 90–120 minutes away). We built our program as a hospital-owned facility, seeing our first patient in 2006. Within 2 years we joined the UC Davis Cancer Care Network and inaugurated our virtual tumor board program with them. UC Davis already had their weekly disease-specific tumor boards scheduled, so it was natural to expand them into a virtual network with four satellite facilities on their existing schedule of Monday-gastrointestinal, Tuesday-genitourinary, Wednesday-thoracic, and Thursday-breast (approximately 80% of all cancer cases come from these four tumor types). By focusing on these four tumor types, we were able to create the necessary infrastructure to manage the remaining tumor types quite well. Participating on these daily tumor boards allowed us to develop a truly collegial relationship with the medical and support staff of a National Cancer Institute–designated comprehensive cancer center, thereby facilitating second opinions, advanced surgical referrals, and advanced therapy such as stem cell transplantation, as well as accrual to active clinical trials both at UC Davis and locally. Preparation time for the tumor boards has now become quite minimal as our comfort level has stabilized.[6,7]

Once our physicians became more secure in front of a camera, we were able to establish four remote telemedicine locations. Each location is staffed by a nurse practitioner or physician assistant in an exam room outfitted with appropriate telecommunication equipment. Chemotherapy and radiotherapy are still given at our primary site, but the follow-up visits, including the “day-10 CBCs,” are done via telemedicine. Our patients greatly appreciate the ability to stay local instead of driving 1 hour in a snowstorm for a routine office visit. For those patients getting chemotherapy or radiotherapy, we obtained philanthropic support enabling our patients to have a hotel room for $25/night, which is often less than the cost of fuel.

Just as the needs of bush pilots in Alaska helped drive the development of current navigation and communication systems used throughout the world, addressing the needs of remote rural cancer patients can drive the creation of improved systems for all patients with a real or perceived disparity in access to quality care.

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. 

Charlton M, Schlichting J, Chioreso C, et al. Challenges of rural cancer care in the United States. Oncology (Willston Park). 2015;29:633-40, 644.

Ward MM, Ullrich F, Matthews K, et al. Access to chemotherapy services by availability of local and visiting oncologists. J Oncol Pract. 2014;10:26-31.

 Ward MM, Ullrich F, Matthews K, et al. Where do patients with cancer in Iowa receive radiation therapy? J Oncol Pract. 2014;10:20-5.

Forefront: Mayo Clinic Cancer Center’s Online Magazine. Rural women less likely to get radiation therapy after lumpectomy. 

http://www.mayo.edu/research/forefront/rural-women-less-likely-get-radiation-therapy-after-lumpectomy

 Newkirk V, Damico A. The Henry J. Kaiser Family Foundation. The Affordable Care Act and insurance coverage in rural areas. 2014. Available at: 

http://kff.org/uninsured/issue-brief/the-affordable-care-act-and-insurance-coverage-in-rural-areas/

 Heifetz LJ, Christensen SD, Devere-White RW, Meyers FJ. A model for rural oncology. J Oncol Pract. 2011;7:168-71.

 Bold RJ, von Friederichs-Fitzwater MM, Kugelmass J, et al. Virtual tumor boards: community university collaboration to improve quality of care. Commun Oncol. 2013; 10:310-5.

As technology has affected every segment of society, we in the oncology community have a responsibility to make every effort to utilize these advances to enable the broadest possible outreach to our patient population in a continual process of quality improvement. 

Country Docs With City Technology Can Address Rural Cancer Care Disparities

The evidence is overwhelming. The completion of four phase III randomized trials by the Gynecologic Oncology Group (GOG), the reporting of three of these trials in prominent high-impact journals, and the release of the 2006 National Cancer Institute consensus statement all support the use of intraperitoneal (IP) therapy.[1] Articles in the “pro-IP” publications-

-are always followed by waves of enthusiasm for this approach, but sadly not by a paradigm shift. The evidence suggests that few centers offer IP therapy routinely. Why? The answer may be that oncologists simply don’t know what to do. There have been three completely distinct regimens, none of which has been used in the outpatient setting. As outlined in the article by Drs. Oseledchyk and Zivanovic,[2] most centers providing IP therapy do not use GOG-approved dose-reduced regimens.[3,4] Very little research has been done on how to administer cytotoxics to the peritoneum, an important issue for the community oncologist in an outpatient center. The fact is, the drugs are old and the approach is old. The emphasis in oncology is always, as it should be, on the next breakthrough: paclitaxel in the 1990s, bevacizumab in 2000s, and perhaps immunotherapy in the next decade.

But healthcare reform may place a new emphasis on outcomes rather than new, exciting (and expensive) targeted drugs. With the push for Medicare to bundle payments for cancer care, less expensive approaches will certainly get more attention. In addition, pay-for-performance incentives will likely drive cancer treatment more toward purely evidence-based treatment pathways. This could be the right time to develop IP therapy for our community oncology networks. In the meantime, is there a new kid on the IP therapy block?

A small group of surgical oncologists in the 1990s began to explore the use of heated cytotoxic therapy administered as a single infusion intraoperatively. The outcomes and toxicities have been mixed at high-grade cancers. However, retrospective data and a few randomized trials seem to suggest that hyperthermic IP chemotherapy (HIPEC) is efficacious for well-differentiated gastrointestinal malignancies with very small–to–microscopic-volume disease. In ovarian cancer, HIPEC has been prospectively studied by groups in Italy and France; in addition, a few US centers, including Memorial Sloan Kettering and the University of California Irvine Chao Center, have undertaken prospective trials to define the role of HIPEC in ovarian cancer. There is much to be done before the level of evidence supporting HIPEC can approach the sizable body of existing data for ovarian cancer IP therapy in an evidence-based paradigm.

Still, Oseledchyk and Zivanovic provide valuable insight as to the possible role of HIPEC as an “alternative” IP therapy in ovarian cancer. Their article explores eloquently and thoroughly the issues that prevent the adoption of HIPEC as a replacement for traditional IP therapy. As the authors state, little support for the approach can be gained without a published prospective randomized trial in an ovarian cancer population. It is likely that the added complexity of HIPEC and the training required to manage HIPEC in ovarian cancer centers are preventing further exploration by more centers until there is evidence to support such efforts. Among the obstacles impeding wider use of HIPEC in ovarian cancer is the requirement for extremely small disease volume. Residual disease of a few millimeters or less is currently accepted as a requirement for HIPEC to be effective. It is hard to know exactly how many ovarian cancer patients have such small-volume residual disease following cytoreduction. However, most ovarian cancer surgeons have accepted 1 cm as “optimal” for treatment, a disease volume far too large for HIPEC to be effective. For this reason, we feel HIPEC may be better studied in consolidation or at interval cytoreductions where small-volume residual disease is common and hard to treat effectively.[5]

Now that the fourth GOG phase III study has closed and its data are maturing, we hopefully will soon have a fourth new, dose-reduced outpatient IP regimen. The results of GOG 252 may or may not validate the IP approach to the satisfaction of the modern community-based oncologist, but we hope they will achieve this goal. Pending the results of GOG 252, more exploration of the HIPEC approach in ovarian cancer should be encouraged, perhaps as a replacement for IP therapy, but more likely as an additional option for consolidation of primary or recurrent disease.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

 Trimble EL, Alvarez RD. Intraperitoneal chemotherapy and the NCI clinical announcement. Gynecol Oncol. 2006;103(2 suppl 1):S18-S19.

 Oseledchyk A, Zivanovic O. Intraoperative hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer. Oncology (Williston Park). 2015;29:695-701, 706.

 Naumann RW, Sukumvanich P, Edwards RP. Practice patterns of intraperitoneal chemotherapy in women with ovarian cancer. Gynecol Oncol. 2009;114:37-41.

 Lesnock JL, Richard SD, Zorn KK, et al. Completion of intraperitoneal chemotherapy in advanced ovarian cancer and catheter-related complications. Gynecol Oncol. 2010;116:345-50.

 Edwards RP. Is hyperthermic intraoperative peritoneal chemotherapy and systemic chemotherapy as effective as standard intraperitoneal chemotherapy: time for a prospective trial? Gynecol Oncol. 2011;122:207-8.

The evidence suggests that few centers offer IP therapy routinely. Why? The answer may be that oncologists simply don’t know what to do. There have been three completely distinct regimens, none of which has been used in the outpatient setting.

The Legacy of Intraperitoneal Therapy in Ovarian Cancer: Why Are We Never  Satisfied With the Answer

Despite the clearly established overall health benefits of exercise, its role in reducing prostate cancer risk is unclear. Whereas some studies found often dramatic reductions in prostate cancer risk,[1-3] others found no effect.[4-6] Naturally, for men who do develop prostate cancer, the question is no longer whether exercise can prevent prostate cancer but rather whether it can prevent prostate cancer progression. Unfortunately, we have little evidence on which to make recommendations. Given the limited availability of data in this setting, a recent review of the literature evaluated observational studies and clinical trials addressing the impact of physical activity and exercise on patients at different stages of prostate cancer.

In this issue of ONCOLOGY, Dr. Ramalingam and colleagues provide a concise overview of evidence that physical activity and exercise benefit men with prostate cancer.[7] Specifically, the authors first discuss the Prostate Cancer Lifestyle Trial, which randomized patients with low-grade prostate cancer to an intensive lifestyle program that included a vegan diet supplemented with soy, fish oil, vitamin E, selenium, and vitamin C; stress management; moderate aerobic exercise; and a 1-hour support group weekly vs a placebo arm with no intervention.[8] At 1-year follow-up, those who had adhered to the total lifestyle intervention had decreased levels of prostate-specific antigen and a lower likelihood of undergoing treatment. Differences in treatment rates were maintained up to 2 years.[9] While studies with longer follow-up are warranted, the Prostate Cancer Lifestyle Trial shows the promise of lifestyle changes in affecting prostate cancer progression. However, it should be noted this was not an exercise study, but rather a global lifestyle trial. Of key importance is that men in the intervention group lost 10 pounds, on average. Given that weight loss slows prostate cancer growth in animal models and likely has the same effect in humans,[10] it is conceivable that the entire benefits of the intervention were due to weight loss and not to exercise. While exercise clearly has metabolic benefits, exercise alone is usually ineffective for achieving weight loss.[11]

Dr. Ramalingam and coauthors further summarized the data from three large observational studies that found inverse associations between physical activity and prostate cancer progression, as well as overall and prostate cancer–specific mortality, among men with localized disease. First, a substudy of 1,455 men with localized prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database showed that men who walked briskly for 3 hours weekly or more had a 57% lower rate of progression, defined as biochemical recurrences, secondary treatments, bone metastases, and prostate cancer deaths, than men who walked at an easy pace for less than 3 hours per week.[12] Furthermore, among 2,705 men with nonmetastatic prostate cancer from the Health Professionals Follow-Up Study, those with at least 3 hours per week of vigorous activity had a 61% reduced risk of prostate cancer–specific mortality compared with less active men.[13] Of note, this benefit was not observed for men with lower physical activity levels. As Dr. Ramalingam and coauthors mention, further suggestion that exercise may have prostate cancer benefits comes from the National Prostate Cancer Register of Sweden, a large study of 4,623 men in which improved prostate cancer–specific survival was seen with as little exercise as walking/bicycling at least 20 minutes daily or exercising at least 1 hour per week.[14] On the whole, these studies suggested that some physical activity is better than none when assessing non–prostate cancer-related outcomes. However, at least some studies suggest that to gain prostate cancer–specific benefits, higher intensity and more prolonged activity may be required. Although these results look promising, these are observational studies with self-reported assessments of physical activity, which generate major concerns about confounding factors (eg, men who exercise may be more health-conscious and therefore seek care earlier and have better nutrition), as well as reverse causation (eg, patients with advanced cancer were too sick to exercise); randomized controlled studies are needed to prove these benefits. Moreover, the effect of physical activity in men with advanced cancers remains to be studied.

In their review, Dr. Ramalingam et al further explored the effect of physical activity on men receiving radiation and androgen deprivation therapy (ADT). While aerobic exercise improved short-term fatigue and fitness in men undergoing radiation therapy, resistance exercise improved long-term fatigue, quality of life, and muscle strength.[15] For men on ADT, resistance exercise improved muscle strength, fitness, and quality of life; and unlike aerobic exercise, it mitigated the loss of lean body mass caused by androgen deprivation.[16,17] Given these benefits, we believe exercise should be considered the standard of care for men with prostate cancer undergoing radiation and ADT. For these men, appropriately prescribed exercise regimens, including both aerobic and resistance exercises, may ameliorate a range of treatment-induced side effects. Further study is required, however, to determine whether exercise improves cancer control.

While Dr. Ramalingam and colleagues provided abundant evidence supporting the health benefits of physical activity in general, this relationship is well-known. Whether physical activity specifically slows prostate cancer growth remains to be determined. Moreover, should physical activity indeed slow prostate cancer progression, the authors did not discuss the mechanisms by which this may occur. Although precise biological pathways remain to be fully elucidated, the potential beneficial effects of physical activity may be mediated by a variety of mechanisms-including modulation of circulating factors such as insulin and growth factors, decrease in adipose tissue, reduction of inflammation and oxidative stress, modulation of tumor blood flow, and improvement of immune function.[18] In vitro studies from the Prostate Cancer Lifestyle Trial showed that the growth of LNCaP (lymph node carcinoma of the prostate) cells was inhibited almost eightfold by serum from patients in the intervention group compared with serum from the control patients.[8] This effect has been attributed to the increased serum levels of tumor suppressor proteins, such as insulin-like growth factor binding proteins 1 and 3, and decreased serum levels of tumor-promoting proteins, such as epidermal growth factor and insulin-like growth factor 1, leading to activation of cellular p53, p21, and caspases, which collectively results in slowed tumor growth. In addition, physical activity may affect prostate cancer growth by reducing inflammation. Physical activity lowers levels of inflammatory factors such as C-reactive protein and interleukin-6; increases levels of anti-inflammatory cytokines; and inhibits production of pro-inflammatory cytokines, which have been shown to promote cell proliferation and inhibit apoptosis of prostate cancer cells in vitro.[19]

Despite this oversight, we do applaud the authors for providing practical methods by which clinicians can assess and implement physical activity regimens for their patients with prostate cancer. Given the overall health benefits of physical activity, there is no doubt that patients should be exercising, although as previously mentioned, it is unclear at this time whether this intervention truly has an impact on prostate cancer progression. Dr. Ramalingam and coauthors recommend the 5 A’s (ask, advise, assess, assist, and arrange) strategy based on its use in smoking cessation programs. Just as successful smoking cessation begins with identifying smokers and appropriate interventions based upon the patient’s willingness to quit, the 5 A’s may be a framework for engaging prostate cancer patients in conversations about their levels of physical activity.

In summary, the authors highlight data from observational studies and clinical trials addressing the impact of physical activity and exercise on men with prostate cancer. While larger randomized controlled trials are required to confirm and expand current findings, the authors present convincing evidence that men with localized disease should stay physically active to improve their overall health and mitigate the side effects of radiation treatment and ADT. Whether these behavior changes will improve their cancer prognosis is unclear. However, even if physical activity has no effect on the cancer, given the well-known benefits for cardiovascular and overall health, all men living with prostate cancer should be advised to be physically active.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article

 Orsini N, Bellocco R, Bottai M, et al. A prospective study of lifetime physical activity and prostate cancer incidence and mortality. Br J Cancer. 2009;101:1932-8.

 Antonelli JA, Jones LW, Banez LL, et al. Exercise and prostate cancer risk in a cohort of veterans undergoing prostate needle biopsy. J Urol. 2009;182:2226-31.

 Pierotti B, Altieri A, Talamini R, et al. Lifetime physical activity and prostate cancer risk. Int J Cancer. 2005;114:639-42.

 Patel AV, Rodriguez C, Jacobs EJ, et al. Recreational physical activity and risk of prostate cancer in a large cohort of U.S. men. Cancer Epidemiol Biomarkers Prev. 2005;14:275-9.

 Wiklund F, Lageros YT, Chang E, et al. Lifetime total physical activity and prostate cancer risk: a population-based case-control study in Sweden. Eur J Epidemiol. 2008;23:739-46.

 Littman AJ, Kristal AR, White E. Recreational physical activity and prostate cancer risk (United States). Cancer Causes Control. 2006;17:831-41.

 Ramalingam S, Pollak KI, Zullig LL, Harrison MR. What should we tell patients about physical activity after a prostate cancer diagnosis? Oncology (Williston Park). 2015;29:680-88, 694.

 Ornish D, Weidner G, Fair WR, et al. Intensive lifestyle changes may affect the progression of prostate cancer. J Urol. 2005;174:1065-9.

 Frattaroli J, Weidner G, Dnistrian AM, et al. Clinical events in prostate cancer lifestyle trial: results from two years of follow-up. Urology. 2008;72:1319-23.

 Allott EH, Masko EM, Freedland SJ. Obesity and prostate cancer: weighing the evidence. Eur Urol. 2013;63:800-9.

 Boule NG, Haddad E, Kenny GP, et al. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA. 2001;286:1218-27.

 Richman EL, Kenfield SA, Stampfer MJ, et al. Physical activity after diagnosis and risk of prostate cancer progression: data from the cancer of the prostate strategic urologic research endeavor. Cancer Res. 2011;71:3889-95.

 Kenfield SA, Stampfer MJ, Giovannucci E, Chan JM. Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study. J Clin Oncol. 2011;29:726-32.

 Bonn SE, Sjolander A, Lagerros YT, et al. Physical activity and survival among men diagnosed with prostate cancer. Cancer Epidemiol Biomarkers Prev. 2015;24:57-64.

 Segal RJ, Reid RD, Courneya KS, et al. Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer. J Clin Oncol. 2009;27:344-51.

 Santa Mina D, Alibhai SM, Matthew AG, et al. A randomized trial of aerobic versus resistance exercise in prostate cancer survivors. J Aging Phys Act. 2013;21:455-78.

 Alberga AS, Segal RJ, Reid RD, et al. Age and androgen-deprivation therapy on exercise outcomes in men with prostate cancer. Support Care Cancer. 2012;20:971-81.

 Wekesa A, Harrison M, Watson RW. Physical activity and its mechanistic effects on prostate cancer. Prostate Cancer Prostatic Dis. 2015 Mar 24. [Epub ahead of print]

 Haverkamp J, Charbonneau B, Ratliff TL. Prostate inflammation and its potential impact on prostate cancer: a current review. J Cell Biochem. 2008;103:1344-53.

Despite the clearly established overall health benefits of exercise, its role in reducing prostate cancer risk is unclear. Whereas some studies found often dramatic reductions in prostate cancer risk, others found no effect.

Should Men Diagnosed With Prostate Cancer Hit the Gym?

Treatment of advanced ovarian cancer remains a challenge, since the majority of patients will develop recurrences, often most evident on peritoneal surfaces. The current conventional intraperitoneal (IP) chemotherapy, defined mostly in three published phase III trials of the Gynecologic Oncology Group (GOG), plus the largest and yet to be analyzed GOG 252 trial, was designed to maximize platinum dose intensity in the presence of microscopic or small-volume residual disease on peritoneal surfaces after surgery, and prior to the emergence of substantial platinum resistance.[1-3] Although results from increased dose intensity achievable by intravenous (IV) platinum-based therapy appeared to reach a plateau in efficacy (but not in major toxic effects-best documented in extensive carboplatin studies),[4-6] the substantially greater IP dose intensity delivered to cells on peritoneal nodules could lead to more efficient eradication in areas of early and life-threatening treatment failures, without greater dose-limiting toxicities. The clinical evidence supporting the efficacy of this conventional IP cisplatin-based chemotherapy is well established, and a recent update of the last two published studies by the GOG provide irrefutable evidence of an improvement in overall survival (with an adjusted hazard ratio of 0.76) compared with IV cisplatin + paclitaxel.[7] However, despite improved survival with IP therapy (which led to the 2006 clinical announcement by the National Cancer Institute in support of IP chemotherapy as standard of care for patients with advanced optimally cytoreduced disease),[8] it has not been widely adopted into routine clinical practice. Reasons for this include variations in the three IP regimens that were declared superior, the inadequacy of the IV cisplatin + paclitaxel control in GOG 114 and GOG 172, the added 2 cycles of high-dose IV carboplatin in GOG 114, and concerns over poor patient tolerability, particularly in GOG 172, including neurotoxicity and catheter-related complications with IP therapy (not surprisingly, when IP paclitaxel was added on day 8 following administration of IP cisplatin, 100 mg/m

, on day 2 of each cycle). Current directions for administration of this conventional GOG IP therapy include testing a decreased dose of cisplatin to 75 mg/m

, omission of IP paclitaxel, substitution of IP carboplatin for cisplatin, and use of bevacizumab to improve retention of chemotherapy within nodules in the peritoneal cavity.[9] Encouraging pilot studies, such as those that added IP bortezomib to IP carboplatin as a means of overcoming platinum resistance (NCT01074411), warrant future consideration. Another potential role for IP cisplatin also worthy of consideration is as consolidation chemotherapy after neoadjuvant chemotherapy with interval debulking surgery in bulky advanced presentations.[10,11] The validity of these approaches needs to be tested in the phase III setting, coupled with translational studies assessing platinum resistance.[12]

Drs. Oseledchyk and Zivanovic provide an overview of the role of hyperthermic IP chemotherapy (HIPEC) in advanced ovarian cancer and cite clinical trials that range from feasibility studies to randomized phase II and III trials-most of them in the recurrent setting, with patients likely exhibiting some degree of platinum resistance relative to the sensitivity to platinum agents observed at presentation (even if designated platinum-sensitive).[13] HIPEC, as initially developed by Dr. Paul Sugarbaker, was meant to control the local growth of mucinous adenocarcinomas of the peritoneal cavity that are notoriously refractory to chemotherapy, and often subjected to repeated palliative surgeries.[14] Sugarbaker’s impressive survival results in this area are suggestive of better control of the disease after surgery plus HIPEC than after surgery alone. Now HIPEC is increasingly being used for a number of malignancies that present with peritoneal carcinomatosis, including gastric, colorectal, appendiceal, and pancreatic cancers, and pseudomyxoma peritonei, which are notoriously insensitive to chemotherapy upon recurrence.[15]

Presumably, perioperative perfusion of IP therapy at temperatures around 42°C immediately following maximal cytoreductive surgery enhances the antitumor effects of drugs, including cisplatin, by augmenting cytotoxicity secondary to loss of DNA repair activities.[16] The hypotheses offered to explain the better outcomes are (1) that the procedure capitalizes on the preferred timing of regional therapy immediately after tumor debulking and prior to formation of postoperative adhesions that hinder drug distribution and efficacy, (2) that there is a synergistic antitumor effect of chemotherapy combined with hyperthermia, (3) that hyperthermia reverses platinum resistance, and (4) that hyperthermia enhances the penetration of drugs into tumors.[17-21]

How valid are these hypotheses for ovarian cancer treatment-especially when the recurrence is still sensitive to platinums and other drugs? The experience with HIPEC in ovarian cancer has been primarily limited to heterogeneous retrospective and case-control series, which do not demonstrate an advantage in overall survival over a vast number of clinical trials by the GOG and others. Ongoing studies and those already published show study variations in patient selection (eg, primary or secondary surgery, first or subsequent recurrences, indeterminate histologic subtypes, etc), differences in chemotherapy drugs and doses, and variability in the temperature and length of hyperthermia. Although HIPEC appears to be relatively well tolerated in appropriately selected patient populations, it is not uncommon for severe postoperative morbidity rates to reach 25%.[22] With regard to drug-related complications, we bring attention to cisplatin-related renal toxicity: although this drug is attractive in any late setting of recurrent ovarian cancer, toxicities have been described in several studies with cisplatin use after HIPEC (Table). This raises the key question for subsequent studies: Is the addition of hyperthermia worth the risk of renal toxicity in the absence of greater insight into platinum resistance and its reversal by hyperthermia? Finally, there are currently no published data from well-designed prospective randomized trials or studies that directly compare HIPEC with conventional postoperative IP therapy, which has a proven survival benefit in a specific upfront setting.

In summary, based on the currently available scientific evidence, HIPEC should not be considered a standard therapeutic option after optimal cytoreduction in advanced ovarian cancer, nor should it be offered outside of a clinical trial. Moreover, still not settled is the question of the optimal drug regimen to use for HIPEC, and the contribution of cisplatin to efficacy and toxicity. The review by Drs. Oseledchyk and Zivanovic points to the rationale for studying HIPEC, and several current prospective randomized trials are evaluating HIPEC in both primary and recurrent disease. In addition, the authors mention novel investigations to improve drug delivery or penetration into the peritoneum, including nanoparticle delivery of IP chemotherapy, which warrant further study. Our commentary is designed to remind the reader of the results from GOG studies of IP therapy (without HIPEC) and of the particular need to understand platinum resistance. We also hope to raise awareness of the renal toxicities of IP cisplatin when administered in the setting of HIPEC.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-5.

 Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-7.

 Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

Gore M, Mainwaring P, A’Hern R, et al. Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. J Clin Oncol. 1998;16:2426-34.

Calvert AH, Newell DR, Gore ME. Future directions with carboplatin: Can therapeutic monitoring, high-dose administration, and hematologic support with growth factors expand the spectrum compared with cisplatin? Semin Oncol. 1992;19(1 suppl 2):155-63.

 Jodrell DI, Egorin MJ, Canetta RM, et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol. 1992;10:520-8.

 Tewari D, Java JJ, Salani R, et al. Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2015;33:1460-6.

 National Cancer Institute. NCI issues clinical announcement for intraperitoneal chemotherapy for ovarian cancer. 2006. 

http://ctep.cancer.gov/highlights/docs/clin_annc_010506.pdf

 Kwa M, Jandial D. Modulation of intraperitoneal (IP) chemotherapy in ovarian cancer. Transl Cancer Res. 2014;4:60-9.

 Vergote I, TropÃ© CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363:943-53.

 Andreopoulou E, Chen T, Liebes L, et al. Phase 1/pharmacology study of intraperitoneal topotecan alone and with cisplatin: potential for consolidation in ovarian cancer. Cancer Chemother Pharmacol. 2011;68:457-63.

 Oza AM, Weberpals JI, Provencher DM, et al. An international, biomarker-directed, randomized phase II trial of AZD1775 plus paclitaxel and carboplatin (P/C) for the treatment of women with platinum-sensitive, TP53-mutant ovarian cancer. J Clin Oncol. 2015;33(suppl):abstr 5506.

 Sugarbaker PH. Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy. Int J Hyperthermia. 2007;23:431-42.

 Loggie BW, Thomas P. Gastrointestinal cancers with peritoneal carcinomatosis: surgery and hyperthermic intraperitoneal chemotherapy. Oncology (Williston Park). 2015;29:515-21.

van de Vaart PJ, van der Vange N, Zoetmulder FA, et al. Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines. Eur J Cancer. 1998;34:148-54.

Los G, van Vugt MJ, Pinedo HM. Response of peritoneal solid tumours after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. Br J Cancer. 1994;69:235-41.

 Helm CW, Bristow RE, Kusamura S, et al. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol. 2008;98:283-90.

Christophi C, Winkworth A, Muralihdaran V, Evans P. The treatment of malignancy by hyperthermia. Surg Oncol. 1998;7:83-90.

 Maymon R, Bar-Shira Maymon B, Holzinger M, et al. Augmentative effects of intracellular chemotherapy penetration combined with hyperthermia in human ovarian cancer cell lines. Gynecol Oncol. 1994;55:265-70.

 Classe JM, Glehen O, Decullier E, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for first relapse of ovarian cancer. Anticancer Res. 2015;35:4997-5005.

 Chiva LM, Gonzalez-Martin A. A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer. Gynecol Oncol. 2015;136:130-5.

 Zanon C, Clara R, Chiappino I, et al. Cytoreductive surgery and intraperitoneal chemohyperthermia for recurrent peritoneal carcinomatosis from ovarian cancer. World J Surg. 2004;28:1040-5.

 Di Giorgio A, Naticchioni E, Biacchi D, et al. Cytoreductive surgery (peritoneal procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer. Cancer. 2008;113:315-25.

Cotte E, Colomban O, Guitton J, et al. Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure. J Clin Pharmacol. 2011;51:9-18.

Warschkow W, Tarantino I, Lange J, et al. Does hyperthermic intraoperative chemotherapy lead to improved outcomes in patients with ovarian cancer? A single center cohort study in 111 consecutive patients. Patient Saf Surg. 2012;6:12.

 Zivanovic O, Abramian A, Kullmann M, et al. HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer. Int J Cancer. 2015;136:699-708.

Deraco M, Virzi S, Iusco DR, et al. Secondary cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent epithelial ovarian cancer: a multi-institutional study. BJOG. 2012;119:800-9.

Hakeam HA, Breakiet M, Azzam A, et al. The incidence of cisplatin nephrotoxicity post hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery. Ren Fail. 2014;36:1486-91.

Based on the currently available scientific evidence, HIPEC should not be considered a standard therapeutic option after optimal cytoreduction in advanced ovarian cancer, nor should it be offered outside of a clinical trial. 

Clinical Trials of Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: Unanswered Questions 

In most cases, localized small-cell bladder cancer requires cystectomy for optimal cure rates.

The small-cell undifferentiated or anaplastic variant of bladder cancer presents a challenging clinical problem, both because of its rarity and the consequent paucity of level I data to guide treatment paradigms. Representing only 1% to 2% of incident bladder cancers, depending on the site of reporting, this entity is most likely the product of a stem cell tumor, with differentiation along an unusual pathway.[1] We have previously modeled the existence of a bladder cancer stem cell, demonstrating preclinically and clinically its potential to differentiate along varied pathways, most commonly glandular or squamous.[2,3] There is extensive evidence to support the common clonal origin of small-cell bladder cancer (SCBC) and urothelial cancer.[4] The fundamental biology of SCBC has not yet been elucidated, although the general consensus is that it is a smoking-related disorder, with common aberrant patterns of chromosomes and gene expression, as well as presence of neuroendocrine biochemical markers.[5,6] If this tumor does not have a stem cell origin, it most likely represents de-differentiation from the scattered neuroendocrine cells in the bladder wall.

Analogous to small-cell tumors arising in other sites, such as bronchus and prostate tumors, SCBC is a highly aggressive variant with a propensity for early local invasion and distant metastasis.[1,5] What is somewhat unusual is the frequent coexistence of urothelial carcinoma in situ,[7] a single-layer thick, but a pattern that is notoriously resistant to radiotherapy or chemotherapy, and which usually only responds to surgical resection or intravesical immunotherapy or chemotherapy.

There really is little controversy about the management of metastatic SCBC. Analogous to small-cell tumors arising from other primary sites, the definitive management is chemotherapy. These tumors are initially very responsive to chemotherapy, although responses in metastatic disease usually only last less than a year.[1,5] Active agents include etoposide, carboplatin, cisplatin, paclitaxel, doxorubicin, cyclophosphamide, ifosfamide, and gemcitabine, each with a single-agent objective response rate of 15% to 25%; higher response rates are associated with lymph node and pulmonary disease, and lower response rates are seen in hepatic and osseous metastases.[1,5,8,9] These single agents can be combined into doublet or triplet regimens, yielding somewhat higher response rates and slightly more durable survival figures, but the majority of patients continue to die within the first 1 to 3 years, depending on their responsiveness to chemotherapy and the pattern and extent of disease.[1,5,8,9] Second-line responses are quite common, but usually of much shorter duration. The dramatic progress in lung cancer treatment from the measurement of programmed death ligand 1 (PD-L1) in tumor tissue with its associated predictive value for response to T-cell functional enhancers, such as pembrolizumab, has not yet been applied to SCBC. Occasional immunotherapy responses have been seen in small-cell lung cancer, and it is possible that a similar situation will apply to SCBC. In the domain of novel cytotoxic agents, scant progress has been made since the introduction of gemcitabine into clinical management of small-cell undifferentiated cancers more than a decade ago.

Clinically Localized SCBC: Conventional Approaches

The management of clinically nonmetastatic SCBC is a much more controversial issue.[1,5,10-14] There is general consensus that these tumors respond well to combination cytotoxic chemotherapy, radiotherapy, or combinations of both. Response rates in the range of 40% to 60% have been recorded in response to two-, three-, or four-drug regimens,[1,5,8,9] often in combination with locoregional radiotherapy, although response does not equate with cure. As previously noted, SCBC has a propensity for early metastasis, and up to 40% of clinically nonmetastatic tumors have proven to be resistant to chemotherapy. Approximately 15% to 20% of nonmetastatic cases of SCBC can be cured by chemotherapy alone or by the combination of chemotherapy and radiotherapy. Similarly, objective response to radiotherapy alone may be as high as 50% to 70%, sometimes leading to cure.

In each instance of SCBC, one of the greatest challenges is posed by the propensity for early visceral metastasis, as well as the proclivity of these tumors to lodge micrometastases within the brain, often manifesting themselves well after completion of initial staging and treatment. As a result, cure rates can be disappointingly low. Given the high initial response rates and potential for a significant proportion of long-term survivors who received chemoradiation, it has been suggested that prophylactic cranial irradiation is a reasonable option that may prolong survival, analogous to the situation in small-cell undifferentiated lung cancer. This has not become standard practice, but is being increasingly explored; however, the lower frequency of brain metastases from SCBC compared with the lung cancer equivalent has precluded this from being viewed as any standard of care.[15]

It has conventionally seemed very attractive to avoid the mutilation and morbidity of cystectomy in the context of a relatively poor potential for cure,[12-14] and thus an emphasis has been placed on radiotherapy alone, chemotherapy alone, or combinations of the two.

Clinically Localized SCBC: The Role of Surgery

“Primum non nocere”-above all, do no harm-is a valid and valued principle of ancient and modern medicine. Given the significant morbidity and potential occasional mortality from the operative removal of the bladder, it is particularly important to establish whether metastases are already present when this option is being considered. There are well-established limitations to the clinical staging of small-cell malignancy, adding to the importance of ensuring that very clear goals of therapy are implemented. The results of cystectomy alone for SCBC have been quite disappointing,[5,10-12] with modest long-term survival figures.

For the elderly patient for whom quality of life and safety are paramount, the role of cystectomy assumes a lesser importance. However, for the patient (especially those who are younger and more robust) for whom length of survival is the key determinant, the majority of available data suggest that initial chemotherapy, followed by cystectomy, offers the greatest potential for cure.[1,5,7,16] It should be emphasized that this literature is heavily influenced by data recycled from MD Anderson Cancer Center, although it is important to note that they have the largest database of such cases. Of particular interest is a review of the National Cancer Data Base, covering all documented cases between 1998 and 2010, which showed a 3-year survival of 53% among patients who received neoadjuvant chemotherapy followed by cystectomy-the best outcome seen[12]; that said, the potential for case selection bias was substantial.

A very important factor is that 30% to 40% of SCBC cases are associated with coexistent carcinoma in situ,[7] which tends to be resistant to chemotherapy and radiotherapy. This connection has been missing from the isolated case reports and case series with only small numbers. This increases the importance of surgical resection, although it is not completely clear whether deep transurethral resection could be a sufficient replacement for radical cystectomy. Given the potential for multisite involvement of carcinoma in situ, it seems that cystectomy is the most prudent option.

It has also been reported that cystectomy followed by adjuvant chemotherapy is another effective option, with a 40% 5-year survival rate compared with 23% for surgery alone.[16,17] Once again, the potential for case selection bias and differences in supportive and salvage therapies is substantial; a randomized clinical trial would be needed to resolve this issue.

Regrettably, there are no level I data, and relatively weak level II data, with significant risk of case selection bias, to support the view that surgery is an essential part of treatment of nonmetastatic SCBC. Data from large databases, such as the Surveillance, Epidemiology, and End Results program, are limited in their accuracy and utility, and the absence of a differential in outcomes from surgery, radiotherapy, or combined-modality regimens in such reports[18] is probably more an artifact of imperfect data recording and capture than the reality of clinical practice. That said, the cure rate from the small reported series of chemoradiation alone is simply lower than the published cure rate associated with combined chemotherapy (with or without radiation) followed by surgery.

Until one of the cooperative cancer trial groups tackles this difficult problem in a multicenter collaboration, it seems to me that the safest approach for a young and robust patient is to offer initial multi-agent chemotherapy followed by restaging, and then cystectomy for patients without evidence of metastatic disease. In that setting, data from several centers suggest potential long-term survival of greater than 50% to 60%. Analogous to urothelial cancer, the data to support adjuvant chemotherapy are still modest, and I prefer to recommend a neoadjuvant strategy until more information is available about the classical adjuvant approach.

 Fahed E, Hansel DE, Raghavan D, et al. Small cell bladder cancer: biology and management. Semin Oncol. 2012;39:615-8.

 Russell PJ, Wills EJ, Philips J, et al. Features of squamous and adenocarcinoma in the same cell in a xenografted human transitional cell carcinoma: evidence of a common histogenesis? Urol Res. 1988;16:79-84.

 Brown JL, Russell PJ, Philips J, et al. Clonal analysis of a bladder cancer cell line: an experimental model of tumour heterogeneity. Br J Cancer. 1990;61:369-76.

 Cheng L, Jones TJ, McCarthy RP, et al. Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and coexisting urothelial carcinoma. Am J Pathol. 2005;166:1533-9.

 Siefker-Radtke AO, Czerniak BA, Dinneu CP, Millikan RE. Uncommon cancers of the bladder. In: Raghavan D, Blanke CD, Johnson DH, et al, editors. Textbook of uncommon cancer. 4th ed. Hoboken, NJ: Wiley-Blackwell; 2012. p. 23-33.

 Terraciano L, Richter J, Tornillo L, et al. Chromosomal imbalances in small cell carcinomas of the urinary bladder. J Pathol. 1999;189:230-5.

 Lynch SP, Shen Y, Kamat A, et al. Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center. Eur Urol. 2013;64:307-13.

 Mackey JR, Au H-J, Hugh J, Venner P. Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival. J Urol. 1998;159:1624-9.

 Siefker-Radtke AO, Kamat AM, Grossman HB, et al. Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin in small-cell urothelial cancer. J Clin Oncol. 2009;27:2592-7.

 Cheng L, Pan CX, Yang XJ, et al. Small cell carcinoma of the urinary bladder: a clinicopathological analysis of 64 patients. Cancer. 2004;101:957-62.

 Quek ML, Nichols PW, Yamzon J, et al. Radical cystectomy for primary neuroendocrine tumors of the bladder: the University of Southern California experience. J Urol. 2005;174:93-6.

 Patel SG, Stimson CJ, Zaid HB, et al. Locoregional small cell carcinoma of the bladder: clinical characteristics and treatment patterns. J Urol. 2014;191:329-34.

Eswara JR, Heney JM, Wu CL, McDougal WS. Long-term outcomes of organ preservation in patients with small cell carcinoma of the bladder. Urol Int. 2015;94:401-5.

 Mattes MD, Kan CC, Dalbagni G, et al. External beam radiation therapy for small cell carcinoma of the urinary bladder. Pract Radiat Oncol. 2015;5:e17-e22.

 Naidoo J, Teo MY, Deady S, et al. Should patients with extrapulmonary small-cell carcinoma receive prophylactic cranial irradiation? J Thorac Oncol. 2013;8:1215-21.

 Siefker-Radtke AO, Dinney CP, Abrahams NA, et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the MD Anderson cancer experience. J Urol. 2004;172:481-4.

 Kaushik D, Frank I, Boorjian SA, et al. Long-term results of radical cystectomy and role of adjuvant chemotherapy for small cell carcinoma of the bladder. Int J Urol. 2015;22:549-54.

 Schreiber D, Rineer J, Weiss J, et al. Characterization and outcomes of small cell carcinoma of the bladder using the surveillance, epidemiology, and end results database. Am J Clin Oncol. 2013;36:126-31.

POINT: Is Cystectomy Needed for Small-Cell Bladder Cancer?

Radiation therapy with concurrent chemotherapy is an effective treatment strategy for small-cell bladder cancer.

Small-cell bladder cancer (SCBC) is a rare malignancy that accounts for fewer than 1% of all bladder cancer subtypes.[1] The clinical presentation and risk factors for SCBC are identical to the more common bladder histologies, although prognostically these tumors behave more aggressively. Histologically, these tumors are composed of sheets of small, round, blue hyperchromatic cells with little cytoplasm, and they stain positively for neuroendocrine markers (ie, chromogranin, synaptophysin, and neuron-specific enolase).[2] Importantly, 38% to 70% of cases will also exhibit a coexisting non–small-cell carcinoma component, including urothelial carcinoma, adenocarcinoma, or squamous cell carcinoma, supporting the hypothesis that these tumors may arise from a single cancer stem cell that then differentiates into diverse cell types.[3] The rarity of this entity precludes a standard management approach, and it is unclear whether these tumors should be managed in a similar fashion as other bladder histologies or whether treatment should be analogous to smallcell carcinomas of other primary sites. In either case, definitive radiation therapy with concurrent chemotherapy is an appropriate treatment option for localized SCBC.

The standard management of urothelial carcinoma of the bladder is either radical cystectomy or multimodality bladder preservation therapy. Bladder preservation therapy using a multimodality approach, inclusive of maximally complete transurethral resection (TUR), radiation therapy, and concurrent chemotherapy, has demonstrated outcomes comparable with surgical series in many retrospective and prospective studies.[4-9] With appropriate patient selection and an integrated multimodality approach to treatment, bladder preservation rates of 75% to 80% and overall survival rates of 50% to 60% have been reported. Furthermore, the functionality of retained bladders is well-preserved, since long-term urinary morbidity following chemoradiation is low.[5,6] In a series of 112 patients treated with TUR followed by concurrent chemoradiation using cisplatin/5-fluorouracil, 79% of surviving patients with an intact bladder were delighted or pleased with their urinary function.[10] Close surveillance and prompt cystectomy for muscle-invasive recurrence is an essential component that requires patient motivation and multidisciplinary participation for success of this therapy.

Whether similar success with multimodality bladder preservation is achievable with variant histology bladder tumors such as small-cell carcinoma is difficult to know, since published series are small and retrospective. What is known is that small-cell carcinomas appear to behave more aggressively than typical bladder histologies, with higher rates of distant metastases and lower survival rates.[11,12] According to a recent Surveillance, Epidemiology, and End Results analysis, 50% of SCBC cases are diagnosed with locally advanced/metastatic disease.[1] Even with localized disease, the median overall survival rates are poor (< 20 months),[1] suggesting that integration of systemic therapy is crucial to optimal outcomes for SCBC. Additionally, the potential quality-of-life benefit of a bladder-sparing approach is particularly appealing in this setting, since many patients will have distant recurrence and do not necessarily benefit from a more aggressive surgical approach. Alarmingly, curative multimodality treatment for these cancers is currently underutilized and should be considered whenever feasible.[1]

Since the histology and aggressive clinical behavior of SCBC is similar to small-cell carcinoma of the lung, it is reasonable to make management decisions by extrapolating from the lung cancer experience. Small-cell carcinoma of the lung accounts for nearly 15% (~240,000 new cases per year) of all primary pulmonary malignancies and therefore has a larger published experience.[13] Standard management of limited-stage small-cell lung cancer consists of early onset of systemic platinum-based chemotherapy and early integration of local radiation, with surgery having little role. In fact, the superiority of radiotherapy over surgery was established over 40 years ago in a randomized trial comparing surgery (median survival, 6.5 months) and radiation therapy (median survival, 9.9 months).[14] Most chemotherapy strategies integrate etoposide and cisplatin for a minimum of 4 cycles, with improved survival outcomes if thoracic radiation therapy is given early or concurrently with chemotherapy.[15] Additionally, due to the propensity for tumor repopulation, treatment intensification using hyperfractionated accelerated chemoradiation has demonstrated improved survival compared with conventionally fractionated radiation therapy.[16] Continuing advances in both radiation techniques and tailoring chemotherapy remain the focus of thoracic oncologists treating this disease.

Oncology Vol 29 No 9

Implications of the New Face of Head and Neck Cancer

Should Response to Preoperative Therapy Guide Local Management in Node-Positive Breast Cancer?

Country Docs With City Technology Can Address Rural Cancer Care Disparities

The Legacy of Intraperitoneal Therapy in Ovarian Cancer: Why Are We Never Satisfied With the Answer

Should Men Diagnosed With Prostate Cancer Hit the Gym?

Clinical Trials of Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: Unanswered Questions

POINT: Is Cystectomy Needed for Small-Cell Bladder Cancer?

COUNTERPOINT: Is Cystectomy Needed for Small-Cell Bladder Cancer?

Julie M. Vose, MD, President of ASCO-and Editor-in-Chief of ONCOLOGY-Discusses Her New Role and the Importance of Investing Wisely in Cancer Research

Diabetics at Increased Risk of Advanced Breast Cancer