Allie Strickler

The addition of chemotherapy, either adjuvant or induction, to concomitant chemoradiotherapy (CRT) achieved a significantly high survival benefit for patients with locally advanced nasopharyngeal carcinoma (NPC), according to the results of a recent meta-analysis published in the

The analysis showed that, overall, regimens containing concomitant chemotherapy generally ranked better than schedules without concomitant chemotherapy. Moreover, for the treatments that did include CRT, the addition of adjuvant chemotherapy (AC) specifically ranked better than CRT alone. However, those differences in head-to-head comparison were only found to be significant for progression-free survival (PFS) and locoregional control.

Induction chemotherapy (IC), on the other hand, when added to CRT, ranked better than CRT alone for PFS, locoregional control, and distant control.

Despite the fact that the individual patient data Meta-Analysis of Chemotherapy (MAC) in NPC (MAC-NPC) has demonstrated that the addition of concomitant chemotherapy to radiotherapy improves outcomes for patientsincluding overall survival (OS), PFS, locoregional control, and distant control&mdash;controversy remains regarding potential additional benefits of IC or AC to CRT. Current treatment guidelines reflect these lingering controversies, allowing multiple treatment options.

&ldquo;I have a long debate with &lsquo;pure medical oncologists&rsquo; that IC is not a right idea to go even in patients with high metastatic potential,&rdquo; Kwan-Hwa Chi, MD, one of the authors on the study, said in an interview with

. &ldquo;Most physicians regard CRT as nothing but killing cells, but we should look at the things on immunologic points.&rdquo;

Chi also said he thinks of CRT as a method of immunotherapy, such that it can induce immunogenic death.

&ldquo;For example most NPC patients regain immunity against EBV-associated immunity. RT alone usually failed to achieve this goal. The IC initially shrank tumor size but rarely evoked immunity, and might create drug-resistant clones left for CRT, which is difficult to induce successful immunity.&rdquo;

According to Chi, the &ldquo;low intensity&rdquo; AC followed by CRT is a good strategy for these patients, as it maintains the immunity created by CRT.

The MAC-NPC is a meta-analysis of individual patient data that includes most randomized trials conducted up to December 31, 2010, and evaluates the benefit of adding chemotherapy to local treatment in patients with nonmetastatic NPC. The primary endpoint was OS, and secondary endpoints included PFS, locoregional, and distant control. Only severe acute toxicities were assessed in this study, including acute neutropenia, mucositis, weight loss, and hearing loss.

The network consists of a total of 20 trials and 5144 patients. Seven different treatment options were evaluated overall: radiotherapy (RT) alone (which was used as a reference category), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), CRT, IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). Only IC-CRT was not directly compared with RT.

The median follow-up was 7.4 years (6.2 -11.9). Patients in the analysis were mostly male (3826 patients; 74%), under the age of 50 (3177 patients; 62%), and had good performance status (0 in 2743 patients [65%] and 1 in 1404 patients [33%]). Patients most frequently presented with locally advanced tumors (stage III in 2,519 patients [49%]; stage IVA-B in 2,133 patients [42%]; and nonkeratinizing histology [WHO grade I in 196 patients; 4%]).

score of 63%) all had the highest effect on OS. The corresponding absolute benefit at 5 years was, respectively, 12%, 8%, and 6% compared with RT alone.

There was no significant heterogeneity (I

= .53). Compared with RT alone, the HRs (95% CIs) for OS for CRT-AC, CRT, and IC-CRT, were, respectively, 0.65 (0.56-0.75), 0.77 (0.64-0.92), and 0.81 (0.63-1.04). The HRs (95% CIs) of CRT-AC compared with CRT or IC-CRT demonstrated no significant differences, with respective values of 0.85 (0.68-1.05) and 0.81 (0.61-1.07).

The PFS results were generally consistent with OS findings in this study. No heterogeneity (I

= .96) was detected. The 3 best treatments for OS were the same for the PFS endpoint, with CRT-AC ranking as the most effective (

score of 52%). The HRs (95% CIs) of CRT-AC compared with CRT or IC-CRT were, respectively, 0.81 (0.66-0.98) and 0.92 (0.71-1.18).

In terms of locoregional control, the 3 best treatments were IC-RT-AC (

score of 58%), and there was no heterogeneity (I

According to 2 sensitivity analyses for OS in the study, CRT-AC remained the most effective treatment, followed closely by IC-CRT and CRT.

The toxicity analyses showed CRT-AC and RT-AC to be the most toxic regimens for mucositis/hearing loss and neutropenia/weight loss, respectively. This underscores the potential toxicity of AC when administered either alone or in combination with CRT.

Despite those toxicities, Chi supports the use of CRT-AC overall in the treatment of this patient population.

&ldquo;Accordingly, we need CRT plus AC,&rdquo; he said. &ldquo;The risk of IC is high because patients suffered more unnecessary toxicities. However, the AC intensity should not go high to avoid the extra-inflammation from CRT to be boosted, which may further decrease the immunity benefit created from AC.&rdquo;

Ribassin-Majed L, Marguet S, Lee A, et al. What is the best treatment of locally advanced nasopharyngeal carcinoma? An individual patient data network meta-analysis [published online December 5, 2016]

Articles

The addition of chemotherapy, either adjuvant or induction, to concomitant chemoradiotherapy (CRT) achieved a significantly high survival benefit for patients with locally advanced nasopharyngeal carcinoma.

Concomitant Chemoradiotherapy Demonstrates Survival Benefit in Nasopharyngeal Carcinoma

According to Michael F. Press, MD, PhD, new guidelines for the way patients with breast cancer should be classified are a concern, as a small subset of patients are liable to be misclassified and receive the wrong treatment. Press, a member of the College of American Pathologists (CAP), has recommended changes to updated ASCO-CAP guidelines on assessment of

amplification by fluorescence in situ hybridization (FISH).

Press, the Harold E. Lee Chair for Cancer Research in the Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, discussed the new ASCO-CAP guidelines for HER2 FISH testing at the 2017 Miami Breast Cancer Conference. Although the updates have resulted in no changes for approximately 90% to 95% of cases, they will result in potential disagreements for approximately 5% of HER2 breast cancer cases, according to Press.

The guidelines were published in 2013 and 2014 and did not recommend many changes related to testing for the HER2 protein using immunohistochemistry [IHC]. Some minor revisions were made, but they didn&rsquo;t substantially impact the way in which HER2 is evaluated by IHC. On the other hand, the ASCO-CAP guidelines committee did make a number of changes in the way the

gene is evaluated by FISH for gene amplification. These changes have created confusion about whether or not some FISH subgroups are

amplified, known as in situ hybridization (ISH)-positive, or

not amplified, known as ISH-negative. This confusion impacts approximately 5% of women with breast cancer.

Approximately 20% to 25% of breast cancers in women have the

gene alteration, also known as gene amplification. This means that the cancer cells have increased the number of copies of the

gene in each tumor cell. Whereas normal cells have 2 copies of the

gene, cancer cells often have greater than 20 copies per tumor cell. This leads to a great increase in such things as cell migration, cell invasion, and increased cell division. It stimulates the production of new blood vessels, and these cancer cells are much more aggressive than cancers that lack this particular alteration.

The good news is that there are several different HER2-targeted therapies that interfere with the actions of the overexpressed protein on the cell surface. And one class of these would be monoclonal antibodies that are directed against the extracellular domain, such as trastuzumab (Herceptin) and pertuzumab (Perjeta). There are also antibodydrug conjugates (ADCs). There&rsquo;s T-DM1 (trastuzumab emtansine; Kadcyla), which is linked to a biological toxin, so that the drug is directed to tumor cells that overexpress HER2. When the membrane is internalized, the poison that&rsquo;s linked to trastuzumab damages and destroys the tumor cells. Another class of agents is anti-HER2 small molecule inhibitors. Either one of these classes of drugs prevent the continuous stimulation of HER2 in tumor cells.

Because there are drugs that are aimed at

gene amplification and overexpression, it&rsquo;s important to know who among patients with breast cancers has this alteration and who doesn&rsquo;t. In the absence of gene amplification, there is no HER2 overexpression. The ASCO-CAP guidelines for HER2 testing by FISH have created new definitions of what is HER2-positive and what is HER2-negative. And I think these new definitions are problematic.

How are these definitions changing, and what makes them so problematic?

In the past, women were enrolled in clinical trials of HER2-targeted drugs if they had HER2-positive breast cancers. The definition of HER2-positive by FISH in the past referred to a ratio between the number of copies of the

gene, compared with a control gene on the same chromosome arm that was greater than 2. The centromere is the usual control gene for calculation of this ratio. When the ratio of the

gene compared with the centromere (CEP17) is greater than 2, these breast cancers are referred to as

The current ASCO-CAP guidelines for HER2 testing by FISH require consideration of both the

gene copy number per tumor cell. Because the clinical trials used for FDA approval of HER2-targeted therapies did not use this definition, it was not clear how the current ASCO-CAP guidelines definitions correspond to the previous definition of

amplification used for enrollment in the clinical trials.

In order to address this issue, we reanalyzed the

gene amplification status of more than 10,000 women previously enrolled in 3 Breast Cancer International Research Group clinical trials using the current ASCO-CAP guidelines. We found that the HER2 status for approximately 95% of these women&rsquo;s breast cancers was not changed by the new guidelines. However, the HER2 status of approximately 5% of these women was different than the status originally assigned to their cancers.

, and it reported that difference. Although this change in HER2 FISH scoring affects only a minority of the breast cancer population, these 5% of cases constitute 3 of 5 FISH scoring categories created by the new ASCO-CAP guidelines. Our findings indicate all 3 of these subgroups are mislabeled by the guidelines and should be revised.

Do oncologists in this space share your dissatisfaction with the newer guidelines?

Many medical oncologists treating patients with breast cancer are dismayed about the uncertainty the current guidelines create for some of their patients. The ASCO-CAP guidelines FISH group that has created the most confusion is the group classified as ISH-equivocal. These women represent about 4% of all breast cancers. Because a HER2-targeted therapy &ldquo;treat&rdquo; or &ldquo;not treat&rdquo; decision must be made, assignment to an equivocal category is not acceptable for either the patient or her oncologist. Our findings indicate that the breast cancers in this equivocal category are not amplified and women with these cancers have a clinical outcome similar to that of other women whose cancers are considered ISH-negative or

not amplified. Some of these women with ASCO-CAP equivocal breast cancers are, nevertheless, currently receiving HER2-targeted therapy.

The equivocal group has represented a problem that comes up in about 1 out of every 20 patients. For medical oncologists treating patients frequently, this issue arises with great regularity.

The additional problem with this is that the ASCO-CAP guidelines recommend that these patients&rsquo; breast cancers can be analyzed with alternative control genes. As I explained before, there&rsquo;s a numerator of

copy number divided by the chromosome 17 centromere copy number. That ratio in this equivocal category is less than 2. But they [ASCO-CAP guidelines] have also permitted, or even suggested, that alternative genes on the same chromosome could be used in that denominator as comparison controls.

gene is located on the long arm of chromosome 17, the q arm. One could choose other genes that are on that arm for comparison. Retinoic acid receptor alpha is a frequently used gene on that arm. The opposite arm, the p arm, which is the short arm of chromosome 17, has a number of other genes that are used, including the

gene, and the Smith-Magenis Syndrome regionwhich is a birth defect in children that&rsquo;s on that arm&mdash;and there are a couple of other genes that are used and recommended, for example, by the Mayo Clinic and the Cleveland Clinic, as alternative control genes. Many large laboratories are using all of these controls, and when any one of them produces a ratio greater than 2, they&rsquo;re recommending that these patients be considered HER2-positive by ISH. Our review in our lab would be, and has been for a long time, that this is not warranted, because many of those genes on the p arm of the chromosome are deleted.

Breast cancers can increase gene copy number, or they can reduce gene copy number. On the p arm, I mentioned that

is a gene that&rsquo;s present on that arm, and it&rsquo;s mutated in about 20% of human breast cancers. In that setting where it&rsquo;s mutated, the normal copy of TP53 is frequently lost or deleted. So that whole arm of chromosome 17 has relatively frequent deletions of portions of that arm. If you have, say, a numerator that&rsquo;s just a normal value, and you lose one of the 2 comparator genes that&rsquo;s in the denominator, suddenly your ratio, instead of being, say, 1, goes to 2, simply because half of your denominator is lost. It doesn&rsquo;t really reflect that the HER2 gene has increased in copy number. There&rsquo;s a loss of the comparison gene, the control gene.

In that setting, a lot of large commercial laboratories and large institutional laboratories are reporting a ratio greater than 2 and suggesting that these patients are HER2-positive. The patients are then being subjected to a course of chemotherapy and trastuzumab that is consistent with HER2-positive disease. We&rsquo;re suggesting that this is inappropriate, and the data we have on clinical outcomes in our paper also suggest that this is not warranted.

Press MF, Sauter G, Buyse M, et al. HER2 gene amplification testing by fluorescent in situ hybridization (FISH): comparison of the ASCO-College of American Pathologists guidelines with FISH scores used for enrollment in Breast Cancer International Research Group clinical trials [published online August 29, 2016].

Michael F. Press, MD, PhD, discusses&nbsp;the new ASCO-CAP guidelines for HER2 FISH testing.

Patients Liable to Be Misclassified Under New HER2 Gene Testing Guidelines, Expert Says

In the current treatment landscape of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), there is a significant lack of biomarkers to predict recurrence. Additionally, as Matthew E. Spector, MD, notes, the incidence of OPSCC continues to rise.

&ldquo;Due to HPV, people are getting more and more of these types of cancers, and hopefully that will go down once more people get vaccinated, but right now, we&rsquo;re on this big upswing that&rsquo;s probably going to keep going up,&rdquo; said Spector, who is the lead author of a new biomarker study published in

In the study, researchers found that patients whose oropharyngeal cancer recurred had higher levels of antibodies for 2 proteins, E6 and E7, which are found in HPV-driven cancers. These findings highlight the potential for a novel, blood-based marker that could predict when cancer is likely to return.

, Spector, an assistant professor specializing in otolaryngology at the University of Michigan Medical School, discussed the results of this study as well as the pressing need for biomarkers in this patient population.

Please discuss the lack of biomarkers in head and neck cancer, and how that affects the treatment landscape.

Oropharynx cancer is one of the only types of cancer that is really increasing in incidence, especially in head and neck cancer. Due to HPV, people are getting more and more of these types of cancers, and hopefully, that will go down once more people get vaccinated, but right now, we&rsquo;re on this big upswing that&rsquo;s probably going to keep going up. These patients are usually younger, they&rsquo;re healthier, and they have less smoking and drinking history. When we saw this, we needed a way to try to predict which patients would fail therapy, because most patients do pretty well.

Biomarkers in cancer are always a little tricky. There are some really good ones out there. Prostate cancer has a really good blood-based biomarker, as does thyroid cancer. But for head and neck cancer, we&rsquo;ve tried a lot of different things, but we haven&rsquo;t been able to detect it.

What&rsquo;s unique about this cancer is that there are actually viral oncoproteins that are circulating in the blood at some point, so we used that premise to develop this test. The test basically looks at antibodies against those viral oncoproteins, and they&rsquo;re called E6 and E7, and we&rsquo;re able to detect those in patients who are developing recurrence where their antibody levels are actually going up.

How was your study conducted, and what were the most significant findings?

The patients that we used for this trial were before my time here at the University of Michigan, but 1 thing we&rsquo;ve done really well as a group is to collect samples on everybody. We collect blood samples every couple of months, we collect tumor samples when patients initially develop cancer, and then we store these to do studies like this.

We looked back at patients, who were treated from approximately 2000 to 2010, and we looked at their blood samples, and then we divided them into 2 groups: patients who recurred and patients who didn&rsquo;t. Then we used their blood samples to measure these antibody levels.

It was very interesting that, before anyone received any treatment at all for their cancer, everyone had high antibody levelswhich is expected. Everyone has these proteins in their blood, so after treatment, or when you were treated, everyone all saw those levels go down. But the interesting thing was that, for patients who developed recurrence, their antibody levels went back up again&mdash;especially the E7 antibody. So if you take a patient at baseline, and you track their antibody levels, they go down and then up, and that uptick is a chance for us to detect recurrence before we&rsquo;re actually finding it in the patient.

So this is measured more on a patient-by-patient basis, rather than a one-size-fits-all approach?

Yes, this is definitely patient-specific. My antibody levels might be different than yours, and yours might be different than someone else&rsquo;s. But if you track them over time within a patient, the levels should definitely go down and never go back up. And everyone kind of starts at a different level, too, so it&rsquo;s a very personalized way to watch for cancer recurrence.

Are there any next steps planned following these results?

We wrote a phase II clinical trial that we&rsquo;re currently conducting, and we&rsquo;re also in collaboration with other groups to look at bigger sets of patients with this type of cancer to see if we can develop other markers.

Are there any other related trials looking for biomarkers in this particular cancer type that you&rsquo;d like to discuss?

This one is specific for HPV-positive cancer, but we have a second trial that&rsquo;s looking at all head and neck cancers, and it&rsquo;s called MiOTOSeq. That trial is looking at genomic markers, meaning patients who have a gene mutated in their type of cancer, and it&rsquo;s something we can follow or find a treatment for that may not be specific to head and neck cancer.

Like right now, there are maybe a dozen drugs approved for head and neck cancer, but there are thousands of drugs out there that could potentially be used in one of our patients, we just don&rsquo;t know it yet. So the premise of MiOTOSeq is to sequence patients&rsquo; cancer genome, find out where the mutations are, and see if there are any druggable targets against this particular cancerand maybe it&rsquo;s not even a drug used for head and neck cancer, maybe it&rsquo;s traditionally used for something else.

What would you like to see in the next 5 to 10 years in the development of biomarkers in this space?

I would like to see blood-based biomarkers used almost in conjunction with a physical exam to follow cancer patients. If you look at the NCCN guidelines, patients are supposed to be checked every 2 to 3 months in the first year. But if they live far away, maybe they could, instead, send a vial of blood every 2 or 3 months, and then we can test their blood and see if it&rsquo;s clear, and we can possibly change how often we see them, or maybe we detect something and bring them in sooner for a scan. A blood test could revolutionize the way we follow patients after treatment and how we scan them, or how we decide which imaging studies to use, based just on a small test.

Are there any major challenges standing in the way of that kind of revolution?

I think that getting large numbers of patients together to do research is always hard. Head and neck cancer doesn&rsquo;t have as many patients as maybe breast cancer or colon cancer, and so some of these other cancers have already paved the way for this type of research.

Spector ME, Sacco AG, Bellile EL, et al. E6 and E7 antibody levels are potential biomarkers of recurrence in patients with advanced stage human papillomavirus positive oropharyngeal squamous cell carcinoma [published online November 21, 2016].

Matthew E. Spector, MD, discusses a new biomarker study which found that patients whose oropharyngeal cancer recurred had higher levels of antibodies for 2 proteins, E6 and E7, which are found in HPV-driven cancers.

Biomarker May Predict Recurrence in HPV+ Oropharyngeal Cancer

The number of futile laparotomies was reduced with diagnostic laparoscopy in patients with suspected advanced-stage ovarian cancer, according to the results of a recent study published in the

The multicenter, randomized controlled trial, which was conducted in the Netherlands, investigated whether diagnostic laparoscopy could prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced ovarian cancer in whom >1 cm of residual disease will be left following PCS.

&ldquo;We performed the first randomized multicenter study to investigate the role of laparoscopy to make a decision to start with primary cytoreductive surgery or neoadjuvant chemotherapy,&rdquo; study author Marrije R. Buist, MD, PhD, gynecologic oncologist, Department of Gynecologic Oncology, Academic Medical Center, Center of Gynecologic Oncology, in Amsterdam, said in an interview with

&ldquo;Our major finding is that a diagnostic laparoscopy in patients with a suspicion of ovarian cancer with metastases before the start of primary cytoreductive surgery can prevent a primary laparotomy with >1 cm residual disease. In these patients, an interval cytoreductive surgery is a better option after neoadjuvant chemotherapy,&rdquo; added Buist.

Of 201 patients included in the study, 102 were assigned to diagnostic laparoscopy, and 99 patients were assigned to primary surgery. In the laparoscopy arm, 63 of 102 patients (62%) underwent PCS versus 93 of 99 patients (94%) in the primary surgery group. Futile laparotomyresidual tumor with a maximum diameter of >1 cm after PCS&mdash;was observed in 10 of 102 patients (10%) in the laparoscopy group versus 39 of 99 patients (39%) in the primary surgery arm of the trial (relative risk [RR], 0.25; 95% CI, 0.13-0.47;

<.001). Three of 102 patients (3%) in the laparoscopy group underwent both primary and interval surgery, compared with 28 of 99 patients (28%) in the primary surgery group (

Patients between the ages of 18 and 80 with suspected advanced-stage ovarian cancer (FIGO stage IIB or higher) across 8 gynecologic cancer centers in the Netherlands were eligible for the study whenever PCS seemed possible after conventional diagnostic workup. They were randomly assigned (1:1) to either diagnostic laparoscopy or PCS followed by chemotherapy.

An open laparoscopy was performed within 3 weeks after random assignment to inspect the whole abdomen in a systematic fashion. The decision about whether cytoreduction to <1 cm of residual disease was feasible or not was made by the gynecologic oncologist on the basis of the following laparoscopic findings: extensive agglutinated intra-abdominal metastatic disease, extensive serosa invasion of the intestines and/or mesenterial deposits, and irresectable peritoneal metastases at the diaphragmatic level. If PCS could leave at least <1 cm of residual disease, the procedure was performed and then followed by 6 cycles of chemotherapy. If it was deemed not feasible at laparoscopy for PCS to remove all tumor to <1 cm of disease, patients were primarily treated with 3 courses of neoadjuvant chemotherapy followed by interval cytoreductive surgery.

Patients in the arm without diagnostic laparoscopy were all assigned to PCS, with the goal of surgery in all cases being resection of all macroscopic tumors.

In both groups of patients, a second laparotomy was considered after 3 cycles of chemotherapy, in the event that >1 cm of residual tumor was left after the first attempt at surgery.

Follow-up consisted of visits every 3 months for the first 2 years, followed by visits every 6 months for up to 5 years.

The primary outcome measure of the study was a futile laparotomy, which the authors defined as residual tumor with a maximum diameter of >1 cm after PCS. The investigators ultimately sought to guide treatment decisions for either PCS or interval cytoreductive surgery, to reduce the number of patients subjected to multiple laparotomies, and to select patients who are best suited for PCS. Secondary outcomes in the study included adverse events, progression-free survival (PFS) and overall survival (OS).

Of 201 patients included in the intention-to-treat analysis, 102 were assigned to laparoscopy prior to surgery, and 99 patients were assigned to PCS. Baseline characteristics were well balanced between the 2 arms of the study.

In the laparoscopy group, 62% of patients (n = 63) were treated with PCS after laparoscopy, and 38% of patients (n = 39) were assigned to neoadjuvant chemotherapy followed by interval surgery. Reasons for withholding from PCS were mostly attributed to extensive agglutinated intra-abdominal metastatic disease and extensive peritoneal metastases at the diaphragmatic level. In 4 of these patients in the laparoscopy arm, no cytoreductive surgery was attempted due to progression while being treated with chemotherapy or inoperability because of poor general condition.

Ninety-four percent of patients (n = 93) in the primary surgery arm underwent PCS. One patient falsely received a diagnostic laparoscopy, and she was assigned thereafter to neoadjuvant chemotherapy. Five patients in the primary surgery arm of the study experienced deterioration in physical condition after random assignment and were considered unfit to receive PCS. They were treated with neoadjuvant chemotherapy instead. Four patients in this group received interval surgery.

Futile laparotomy that left >1 cm of residual disease following primary surgery was observed in 10 of 102 patients (10%) in the laparoscopy group, versus 39 of 99 patients (39%) in the primary surgery group. In the laparoscopy arm, 27 of 102 patients (27%) had any residual tumor (>0 cm) versus 56 of 99 patients (57%) in the primary surgery arm (RR, 0.47; 95% CI, 0.32-0.68;

<.001). A subgroup analysis of patients with confirmed stage IIIC or IV ovarian cancer showed that only 6 of 71 (8%) patients in the laparoscopy group received a futile laparotomy compared with 32 of 69 (46%) of patients in the primary surgery group.

Four of 102 patients (4%) in the laparoscopy group underwent both primary and interval laparotomy, versus 28 of 99 patients (28%) in the primary surgery group (

The investigators also carried out analyses of the differences in the amount of residual disease per surgical strategy (primary or interval). In the laparoscopy group, no residual tumor was found in 36 of 63 patients (57%) who underwent PCS, versus 37 of 93 patients (40%) in the primary surgery group (

= .006) and in 14 of 34 patients (41%) and 16 of 63 patients (25%) in the subgroup with stage IIIC or IV ovarian cancer, respectively. Complete remission following surgery and chemotherapy was observed in 65 of 99 patients (66%) in the laparoscopy arm versus 65 of 95 patients (68%) in the primary surgery arm.

In the laparoscopy group, the median duration of follow-up was 34.6 months, versus 33.8 months in the primary surgery group. Forty-six patients in the laparoscopy group and 42 patients in the primary surgery group had died at the last time of follow-up (RR, 1.11; 95% CI, 0.99 to 1.25;

= .07). This indicates comparable survival between the 2 treatment arms.

The median PFS was 13.7 months (interquartile range [IQR], 7.1-41.8 months) in the laparoscopy group and 15.2 months (IQR, 7.2 to >34 months) in the primary surgery group (

= .88), with a hazard ratio of 0.97 (95% CI, 0.69-1.38). The median OS was 44.4 months (IQR, 16.8 to >55 months) in the laparoscopy arm and 46.3 months (IQR, 13.9-52.6 months) in the primary surgery group (

= .94) with a hazard ratio of 1.33 (95% CI, 0.89-1.98).

In terms of safety, 22 patients in the laparoscopy group experienced a grade 3 or 4 adverse event versus 26 patients in the primary surgery group (RR, 0.82; 95% CI, 0.50-1.35;

Rutten MJ, van Meurs HS, van de Vrie R, et al. Laparoscopy to predict the result of primary cytoreductive surgery in patients with advanced ovarian cancer: a randomized controlled trial [published online December 28, 2016].

The number of futile laparotomies was reduced with diagnostic laparoscopy in patients with suspected advanced-stage ovarian cancer, according to the results of a recent study.

Laparoscopy Predictive of Primary Surgery Outcomes in Ovarian Cancer

Patients with endometrial cancer who receive surgery in the first 2 weeks after diagnosis have worse survival outcomes, according to a study recently reported in the

American Journal of Obstetrics and Gynecology

Moreover, an extended delay in surgical treatment was also identified to be a risk factor for mortality in low-risk endometrial cancers and was likely associated with poor access to specialty care.

&ldquo;We suspect that physicians diagnosing endometrial cancer may believe, not unreasonably, that the best thing they can do for those patients is to operate as soon as possible, because if they wait too long the cancer could progress, resulting in a worse outcome,&rdquo; senior author David I. Shalowitz, MD, said in a press release.

&ldquo;But, the results of our study suggest that presurgical care and referring patients to a gynecologic oncologist may be more important,&rdquo; added Shalowitz, who is a fellow in Gynecologic Oncology at the Perelman School of Medicine at the University of Pennsylvania.

The authors of the study suggested that the target interval between diagnosis and surgical treatment of endometrial cancers is &le;8 weeks, though they also stressed that both referral to a surgeon and preoperative optimization should be prioritized over expedited surgery.

The results of the study demonstrated that patients with low-risk cancers had a median survival time of 47.6 months (interquartile range [IQR], 25.8-73.6). The 5-year crude survival was highest when surgery was performed 3 weeks after diagnosis, and survival declined thereafter.

Patients who received surgical treatment during the first and second weeks following diagnosis (11.7%) had a higher risk of death (HR, 1.9; 95% CI, 1.7-2.1) compared with patients who underwent surgery in the third week after diagnosis (HR, 1.1; 95% CI, 1.1-1.2). Even after the researchers adjusted for age, stage, race, year of diagnosis, and additional clinical and health system characteristics, early surgery in the first and second weeks after diagnosis was still independently associated with a higher risk of death.

When surgery was performed 8 weeks postdiagnosis, the mortality risk was significantly higher than baseline and worsened as the interval between surgery and diagnosis increased.

For patients with high-risk cancers, the median survival time was 38.6 months (IQR, 18.9-67.1). As with patients with low-risk endometrial cancers, the 5-year crude survival was highest, again, when patients underwent surgery in the third week after diagnosis. Survival outcomes continued to decline thereafter.

High-risk patients who had surgery during the first and second weeks after cancer diagnosis (15.9%) had a hazard ratio for death of 2.1 (95% CI, 1.9-2.2). Surgery during this interval remained independently associated with death after the study authors adjusted for age, stage, race, year of diagnosis, and additional clinical and health system characteristics.

Surgery after the third week postdiagnosis was not correlated with a statistically significant increase in the adjusted risk of mortality, with the exception of an isolated increase seen in the nineteenth week after diagnosis.

The National Cancer Database provided cases of endometrial cancer between 2003 and 2012 for this study. Low-risk (grade 1 and grade 2 endometrioid histologies) and high-risk (grade 3 endometrioid and all other epithelial histologies) tumors were analyzed separately. The researchers limited the overall analysis to only cases for which there were data that surgery was the only modality pursued, or occurred before any hormonal, radiation, or chemotherapy treatments.

Given the results showing increased mortality risk accompanying surgery given in the first 2 weeks postdiagnosis, the investigators compared clinical and process-based factors for patients who had surgery in that short time period with patients who underwent surgery 3 and 4 weeks after diagnosis.

Patients with low-risk cancers who received surgical treatment in the first week after diagnosis were more likely to be very young or very elderly (<45 years or >85 years), Black, uninsured or with Medicaid insurance, have advanced stage disease, and undergo both diagnosis and treatment at the reporting Commission on Cancer (CoC)&shy;accredited hospital. Plus, these patients were less likely to be treated at high-volume hospitals or be treated with lymphadenectomy.

Patients with high-risk endometrial cancers who had surgery in the first week after diagnosis were more likely to be elderly (>85), Black, uninsured or with Medicaid insurance, have advanced stage disease, and receive both diagnosis and treatment at the reporting CoC institution. Similar to the low-risk patients, they were also less likely to be treated at high-volume hospitals or undergo lymphadenectomy.

When compared with patients treated in the third or fourth week after diagnosis, 30-day postoperative mortality was significantly higher among patients treated in the first or second week post-diagnosis.  For patients with low-risk cancers, this difference was 0.7% versus 0.4% (

<.001), and for patients with high-risk cancers, the difference was 2.5% versus 1.0% (

For patients with low-risk endometrial cancers, the independent associations with added time-to-surgery of at least 1 week were observed with Black race (1.1 weeks; 95% CI, 0.9-1.4), lack of insurance (1.3 weeks; 95% CI, 1.1-1.5), Medicaid insurance (1.7 weeks; 95% CI, 1.5-1.9) and Charlson-Deyo comorbidity score >1 (1.0 weeks; 95% CI, 0.8-1.2).

For patients with high-risk cancers, independent associations with added time-to-surgery of at least 1 week were somewhat similar, as these correlations were observed with lack of insurance (1.4 weeks; 95% CI, 0.9-1.9) and Medicaid insurance (1.4 weeks; 95% CI, 1.1-1.7).

Disease stage was not consistently associated with the interval between diagnosis and surgery for patients with either low- or high-risk cancers.

Shalowitz DI, Epstein AJ, Buckingham L, et al. Survival implications of time to surgical treatment of endometrial cancers [published online December 8, 2016].

Patients with endometrial cancer who receive surgery in the first 2 weeks after diagnosis have worse survival outcomes, according to a recent study.

Expedited Surgery Associated With Worse Outcomes in Endometrial Cancer

According to John A. Martignetti, MD, PhD, it is projected that, by 2030, endometrial cancer will become the third leading cancer for women. As mortality rates continue to climb, there remains a pressing need for effective screening and diagnostics.

The Cancer Genome Atlas (TCGA) carried out a comprehensive, genomics-based analysis of the disease, in which they revealed many of the molecular defects that define this cancer. Based on those findings, Martignetti and his colleagues hypothesized that ultra-deep, targeted gene sequencing may be able to detect somatic mutations in uterine lavage fluid obtained from patients undergoing hysteroscopy as a means of molecular screening and diagnosis.

, Martignetti, an associate professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, and network director for the Laboratory for Translational Research at the Western Connecticut Health Network, discussed this novel genomic analysis and what impact the results could have in the detection, screening, and diagnosis of endometrial cancer.

What was the rationale for conducting this genomic analysis?

If you think about endometrial cancer, it&rsquo;s a cancer where there are 55,000 cases a year. And the incidence is actually increasing, so it&rsquo;s projected by 2030, endometrial cancer will probably have the same number of cases as colorectal cancer for US women. It&rsquo;ll become the third leading cancer site in women by 2030.

What really has not kept pace with those increasing numbers is any way to diagnosis it. Symptoms can include nonmenstrual bleeding, postmenopausal bleeding, pain, weight loss, back pain, things like that. But really, there&rsquo;s no clinically useful molecular markers or diagnostics that are currently available. And really, the only way to make a diagnosis, the gold standard way, is to bring a patient into the OR, and do a hysteroscopy, and that really has not changed.

Clearly, to bring the patient into the OR, it&rsquo;s a big deal because you&rsquo;re talking about the pain, the cost, the time, the risks of general anesthesia, and then you&rsquo;ve got issues of tissue sampling, depending on the age of the patient, whether there&rsquo;s any structural abnormalities, and ultimately, the final interpretation of whether that patient has endometrial cancer or not. It&rsquo;s really a subjective test in the sense that it&rsquo;s a section of tissue sent for histology. There aren&rsquo;t any special stains, no special markers; it&rsquo;s really a subjective call. And depending on where you are, you may be blessed with a great pathologist, or maybe that&rsquo;s something you don&rsquo;t have adequately available.

But there are 2 other interesting forces here. One force is essentially, if you think about a pap smear, they were devised about 70 years ago, and the concept is to touch the cervix and look for cytologic changes that would suggest someone has cervical cancer. Since that test was devised, people have been trying to do a similar thing for endometrial cancer. For a number of reasons, it&rsquo;s just never really worked out well.

A couple of years ago, some people came up with a clever test of using a tampon-like device to look for genetic changes that could be associated with endometrial cancer. It was fairly good, but it wasn&rsquo;t great. Earlier this year, another group actually took patients with endometrial cancer and did this lavage procedure that we&rsquo;ve done in our own study and showed that patients with endometrial cancer did have genetic changes that were discoverable in this lavage.

The other force that made this study timely was, a couple years ago, TCGA sequenced endometrial cancers, and from their sequencing of more than 400 patient samples, they showed that genetic changes within the tumors could predict outcome, and there were specific genes that were mutated in these cancers.

And what specifically did you do in your study?

What we did was different from what&rsquo;s been done before. We took 102 women who were being diagnosedin other words, their physicians were suspicious that the patients might have endometrial cancer because the women may have had postmenopausal bleeding, pain, they might have had ultrasound findings of a mass, but couldn&rsquo;t sort out what it was exactly, but there was a suspicion that there could be cancer there, and they needed to get a hysteroscopy.

A hysteroscope is a long steel tube that has a light source and a camera at the end, and also some ports that you flush saline out of, and then on the other end is the operator to see what&rsquo;s in there, allowing the surgeon on the outside to go into the uterine cavity and see what that cavity looks like. When you do that, the uterus is kind of like a collapsed sac, and the surgeon will blow saline in there just to open the sac up, and what we asked for was essentially that saline that&rsquo;s just dripping out. We asked for a collection of that because we figure, that saline is coating the entire cavity. Can we look at that, bring it back to the laboratory, isolate the DNA in there, and sequence it?

TCGA did 2 very intense and very expensive studies, called whole-genome sequencing, where they sequenced every gene that was there in the tumor, and they did whole-exome sequencing, where it&rsquo;s a fraction of the whole genome, but it&rsquo;s still a very expensive look at essentially 23,000 genes in the body.

Instead of doing that, because we have the TCGA data, we asked our biostatisticians, &ldquo;Hey guys, we can&rsquo;t afford to do $10,000 or $20,000 worth of sequencing on 100 women. But what we could do is, if you could tell us that this is possible, could you find a subset of genes that we can sequence very deeply, with very high coverage, that would give us the same information as doing an entire genome?&rdquo;

And that&rsquo;s what they did. We actually have 2 panels here: 1 panel with 12 genes, and 1 larger panel with 56 genes. So instead of doing 23,000 genes, we did 12 or 56, and we used that to sequence the material we pulled out from these lavages. And the study was set up so that, a patient would come into the OR, we would collect the sample, go to the laboratory, the surgeon who is trying to determine the diagnosis does everything he or she would normally do, collect tissue, send it up to pathology, and then they get a result. At the end, when we finished all of our molecular analyses, we went back to the pathologist and said, &ldquo;Hey, how do our results compare with yours?&rdquo; In other words, we have mutations we identified; are these the patients who have endometrial cancer?

So from those 102 women, it turned out that 7 women had endometrial cancer. Six of those women had stage Ia diseasethe earliest microscopic cancers. You&rsquo;re talking essentially about tumors that are about 2 or 3 millimeters in size. If you look at your ballpoint pen, it&rsquo;s around the size of that. If you think about it, that was found in the uterus, and we were able to find mutations in that lavage just coming from that tip of the tumor. We could show that the genetic approach was very sensitive to identify these mutations, and that had never been done before, to prospectively diagnose cancer in these patients using a genetic test. That was really exciting.

But if that were the whole story, what we would be talking about is a screening test, meaning taking women at a certain stage in their lives, and potentially using something like this to see if we could find endometrial cancer. But when we looked at all of our results, and we looked at the other women who were not diagnosed with endometrial cancer, it turns out that half the women in our study also had these genetic mutations. And that was really surprising because, again, these genes that we&rsquo;ve put on our 2 panels, these are really well established cancer genes, such that when you look at a cancer, having these mutations are very strict identifiers of cancer.

But in these women, we found these mutations, and they did not have a clinical diagnosis of cancer. So we thought, &ldquo;Wait a second, are these women maybe developing early cancer? We&rsquo;ve picked them up before they developed cancer? Or is there something else going on in the biology that we need to reevaluate, and say, maybe, even though these are cancer mutations, it&rsquo;s not the same as having cancer?&rdquo;

You would think that because, historically, if you take 100 women to the OR for a suspicion of endometrial cancer, 5% to 10% of those women, wherever you go in the world, will have cancer. It&rsquo;s not 50%; that would be really high and very unexpected. Again, based on the historical record, maybe in 1 or 2 of these women, we might have picked up a premalignancy.

Are there any next steps planned following the results of this analysis?

We&rsquo;re monitoring these women from the original study to really see what evolves in them. This is just research right now, and the results were kind of unexpected. So we&rsquo;re closely following these women who didn&rsquo;t have the mutations, and the 50 who did, we want to see what happens next.

We&rsquo;re also doing a larger study now with 1000 women, and we&rsquo;re going to be looking across multiple institutions to make sure there&rsquo;s no bias related to location. And we&rsquo;re going deeper with the sequencing to add more tests to the original one to see if we can still develop the screening or diagnostic test and really learn about the biology.

What effect do you think a novel test like this could have on the treatment landscape down the road?

We have to be careful in applying all of these really powerful genomic technologies to screening and diagnostics. For example, here in endometrial cancer, we identified this landscape of previously unknown mutations. So if you were to just kind of go off and do this sequencing, you&rsquo;d be telling half the patients who had this test that they have cancer. And that&rsquo;s obviously not true. There&rsquo;s something else going on there.

In general, when we think about screening and diagnostics using these powerful technologies, we&rsquo;ve got to understand the underlying disease better, first off. Second, if, indeed, 50 women have these cancer-driving mutations, why aren&rsquo;t they developing cancer? Is there something that we don&rsquo;t know or don&rsquo;t appreciate yet about what drives women to develop endometrial cancer? Is there something, a push that hasn&rsquo;t happened, or is there some type of a block that&rsquo;s occurred? If we&rsquo;re seeing this in endometrial cancer, might this be going on in other cancers that we just haven&rsquo;t explored yet?

Nair N, Camacho-Vanegas O, Rykunov D, et al. Genomic analysis of uterine lavage fluid detects early endometrial cancers and reveals a prevalent landscape of driver mutations in women without histopathologic evidence of cancer: a prospective cross-sectional study [published online December 27, 2016].

. http://dx.doi.org/10.1371/journal.pmed.1002206.

John A. Martignetti, MD, PhD, discusses&nbsp;The Cancer Genome Atlas&#39; comprehensive, genomics-based analysis of the endometrial cancer.