Κυριακή, 25 Οκτωβρίου 2020

A NOVEL REGIMEN FOR CERVICAL CANCER

In the Chinese phase II CLAP study reported in the Journal of Clinical Oncology, Lan et al found that the combination of the anti–PD-1 antibody camrelizumab and the VEGFR inhibitor apatinib produced high response rates in previously treated women with advanced cervical cancer.

Study Details

The multicenter study included 45 patients (intent-to-treat population) whose disease had progressed after one or more lines of prior systemic treatment. Patients were enrolled between January and August 2019, and received camrelizumab at 200 mg every 2 weeks and apatinib at 250 mg once daily continuously in 4-week cycles up to a maximum of 24 months of camrelizumab treatment. A total of 41 patients were included in the efficacy-evaluable population. The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors version 1.1. A total of 57.8% of patients had previously received two or more lines of chemotherapy for recurrent or metastatic disease and 67% had PD-L1–positive disease (defined as having a combined positive score > 1).

Responses

Median follow-up was 11.3 months. Objective response was observed in 25 (55.6%) of 45 patients, including complete response in 2 (4.4%). An additional 12 patients (26.7%) had stable disease, yielding a disease control rate of 82.2%. Objective response was observed in 25 (61.0%) of 41 patients in the efficacy-evaluable population. Median duration of response was not reached (95% confidence interval [CI] = 5.6 months–not estimable). At time of analysis, 16 of 25 responses were ongoing, with 71.5% lasting ≥ 6 months and 66.8% lasting ≥ 12 months.

In the intent-to-treat population, median progression-free survival was 8.8 months (95% CI = 5.6 months–not estimable), with a 6-month rate of 57.0%. Median overall survival was not reached (95% CI = 11.6 months–not estimable), with a 9-month rate of 69.2%.

KEY POINTS

  • Objective response was observed in 55.6% of patients.
  • Median duration of response was not reached after median follow-up of 11.3 months.

Objective response rates were 69.0% vs 50.0% (P = .281) among patients with PD-L1–positive vs PD-L1–negative tumors. Median progression-free survival was not reached vs 5.2 months (P = .034). Objective response rates were 77.8% in 30 patients with squamous cell carcinoma and 28.6% in 15 patients with adenocarcinoma.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 71.1% of patients, with the most common being hypertension (24.4%), anemia (20.0%), and fatigue (15.6%). Serious treatment- related adverse events were observed in four patients (8.9%) and consisted of rash in two patients; pneumonitis in one; and neutropenia, anemia, and thrombocytopenia in one patient. Adverse events led to discontinuation of treatment in three patients (6.7%). No treatment-related deaths were observed.

The most common potential immune-related adverse events included grade 1 or 2 hypothyroidism (22.2%) and reactive cutaneous capillary endothelial proliferation (8.9%).

The investigators concluded, “Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with advanced cervical cancer. Larger randomized controlled trials are warranted to validate our findings.”

Xin Huang, MD, of the Department of Gynecologic Oncology, Sun Yat-sen University Cancer Centre, Collaborative Innovation Center for Cancer Medicine, Guangdong, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Chinese National Natural Science Foundation. For full disclosures of the study authors, visit ascopubs.org.

pCR AS PROGNOSTIC FACTOR IN HER2+ BREAST CANCER

A pathologic complete response (pCR) to targeted therapy in HER2-positive breast cancer portends good long-term outcomes, according to final results of the phase 3 NeoALTTO/BIG 1-06 trial. In fact, for the majority of women, pCR appears to be a marker of cure.

The trial was conducted among 455 women with HER2-positive breast cancer tumors measuring at least 2 cm who were randomized to neoadjuvant trastuzumablapatinib, or both drugs in combination, each together with paclitaxel, followed by more chemotherapy and more of the same targeted therapy after surgery.

Relative to trastuzumab alone, trastuzumab plus lapatinib improved rates of pCR, as shown by data published in The Lancet in 2012. However, the dual therapy did not significantly prolong event-free or overall survival, according to data published in The Lancet Oncology in 2014. Findings were similar in an update at a median follow-up of 6.7 years, published in the European Journal of Cancer in 2019.

Study investigator Paolo Nuciforo, MD, PhD, of the Vall d'Hebron Institute of Oncology in Barcelona, reported the trial's final results, now at a median follow-up of 9.7 years, at the 12th European Breast Cancer Conference.

There were no significant differences in 9-year outcomes by specific HER2-targeted therapy. However, in a landmark analysis among women who were event free and still on follow-up 30 weeks after randomization, those achieving pCR with any of the therapies were 52% less likely to experience events and 63% less likely to die. Benefit was greatest in the subset of patients with hormone receptor–negative disease.

"The long-term follow-up confirms that, independent of the treatment regimen that we use – in this case, the dual blockade was with lapatinib, but similar results can be expected with other dual blockade – the pCR is a very robust surrogate biomarker of long-term survival," Nuciforo commented in a press conference, noting that dual trastuzumab and pertuzumab has emerged as the standard of care.

"If we really pay attention to the curve, it's maybe interesting to see that, after year 6, we actually don't see any events in the pCR population. So this means that these patients are almost cured. We cannot say the word 'cure' in cancer, but it's very reassuring to see the long-term survival analysis support the use of pCR as an endpoint," he elaborated.

"Our results support the design of future trial concepts in HER2-positive early breast cancer which use pCR as an early efficacy readout of long-term benefit to escalate or deescalate therapy, particularly for hormone receptor–negative tumors," Nuciforo concluded.

Support for Current Practice

"The study lends support for the current practice of risk-stratifying by pCR as well as making treatment decisions regarding T-DM1 [trastuzumab emtansine], and there hasn't been a big change between 5-year and 9-year outcomes," Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center, commented in an interview.

The lack of late events in the group with pCR technically meets the definition of cure, Carey said. "I think it speaks to the relatively early relapse risk in HER2-positive breast cancer and the impact of anti-HER2 therapy that carries forward. In general, these are findings similar to long-term findings of other trials and I suspect will be the same for any regimen."

Although the analysis of dual lapatinib-trastuzumab therapy was underpowered, the trends seen align with favorable results in the adjuvant APHINITY trial (which combined trastuzumab with pertuzumab) and the neoadjuvant CALGB 40601 trial (which combined trastuzumab with lapatinib), according to Carey. "There has been a trend in every other study [of dual therapy] performed, so this is consistent."

Study Details

NeoALTTO is noteworthy for having the longest follow-up among all neoadjuvant studies of dual HER2 blockade in early breast cancer, Nuciforo said.

He reported no significant difference in survival between the treatment arms at 9 years.

The 9-year rate of event-free survival was 69% with lapatinib-trastuzumab, 63% with lapatinib alone, and 65% with trastuzumab alone. The corresponding 9-year rates of overall survival were 80%, 77%, and 76%, respectively.

However, there were significant differences in event-free and overall survival among women who achieved pCR and those who did not.

"pCR was achieved for almost twice as many patients treated with dual HER2 blockade, compared with patients in the single-agent arms," Nuciforo pointed out. The pCR rate was 51.3% with lapatinib-trastuzumab, 24.7% with lapatinib alone, and 29.5% with trastuzumab alone.

Relative to peers who did not achieve pCR, women who did had better 9-year event-free survival (77% vs. 61%; adjusted hazard ratio, 0.48; P = .0008). The benefit was stronger in hormone receptor–negative disease (HR, 0.43; P = .002) than in hormone receptor–positive disease (HR, 0.60; P = .15).

The pattern was similar for overall survival at 9 years – 88% in those who achieved a pCR and 72% in those who did not (adjusted HR, 0.37; P = .0004). Again, greater benefit was seen in hormone receptor–negative disease (HR, 0.33; P = .002) than in hormone receptor–positive disease (HR, 0.44; P = .09).

"Biomarker-driven approaches may improve selection of those patients who are more likely to respond to anti-HER2 therapies," Nuciforo proposed.

From 6 years onward, there were no additional fatal adverse events or nonfatal serious adverse events recorded, and no additional primary cardiac endpoints were recorded.

The study was funded by Novartis. Nuciforo and Carey disclosed no conflicts of interest.

SOURCE: Nuciforo P et al. EBCC-12 Virtual Conference, Abstract 23.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

ASTRO GUIDELINES FOR RECTAL CANCER

A new clinical guideline from the American Society for Radiation Oncology (ASTRO) provides guidance for physicians who use radiation therapy to treat patients with locally advanced rectal cancer. Recommendations outline indications and best practices for pelvic radiation treatments, as well as the integration of radiation with chemotherapy and surgery for stage II/III disease. The guideline, which replaces ASTRO's 2016 guidance for rectal cancer, was published in Practical Radiation Oncology.

Colorectal cancer is the second most common cause of cancer death in the United States, and half of new colorectal cancer diagnoses are in people age 66 or younger. Rectal cancer diagnoses account for nearly one-third of colorectal cancers; an estimated 43,340 adults will be diagnosed with rectal cancer in 2020. Although rectal cancer incidence and mortality rates have dropped among older adults in recent years, they have increased for those younger than age 55.

Standard treatment for locally advanced rectal cancer generally involves chemoradiation therapy or short-course radiation without chemotherapy, followed by tumor removal surgery and additional chemotherapy. More recently, several trials have shown potential for emerging paradigms, such as changing the sequencing of treatments or omitting portions of treatments for select patients.

Key Recommendations

The guideline addresses patient selection for radiation therapy, delivery of pelvic radiation treatments, options for nonoperative management of locally advanced rectal cancer, and guidance for follow-up care:

  • Neoadjuvant radiation therapy is strongly recommended for patients with clinical stage II/III rectal cancer to reduce their risk of locoregional recurrence. Radiation therapy for locally advanced rectal cancer should be performed before rather than after surgery. Radiation may be omitted in favor of upfront surgery for some patients at low risk of recurrence, after discussion by a multidisciplinary care team. Clinical staging involving a physical exam and pelvic magnetic resonance imaging is critical to determine which patients should receive neoadjuvant radiation therapy.
  • For patients who require neoadjuvant radiation therapy, both conventionally fractionated radiation and short-course radiation are recommended equally, given high-quality evidence for similar efficacy and patient-reported quality of life outcomes with each treatment. The guideline specifies optimal dosing, fractionation, and delivery techniques for radiation therapy.
  • Recommendations address how to incorporate chemotherapy into the preoperative setting for patients who are at high risk of recurrence and who would likely benefit from the additional treatment using a total neoadjuvant therapy approach. Recommendations also address other sequencing and timing issues for radiation, chemotherapy, and surgery, with specific attention to treatment tolerability and potential downstaging.
  • Organ preservation approaches (ie, nonoperative management and local excision) may present an alternative to radical surgery for select patients, especially those who would have a permanent colostomy or inadequate bowel continence after surgery. The guideline outlines specific criteria for situations where surgery can be avoided, as well as long-term surveillance and care for these patients.

Disclosure: For full disclosures of the study authors, visit practicalradonc.org.

PROGNOSIS OF PRECANCEROUS PANCREATIC LESIONS

NEW YORK (Reuters Health) - Invasive pathology and positive surgical margins are associated with worse outcomes after resection of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, researchers in South Korea report.

"Outcomes of survival and recurrence differed according to initial pathology and margin status after resection in patients with IPMN," Dr. Hyeong Seok Kim of Seoul National University College of Medicine told Reuters Health by email.

"However, even in patients with low-grade dysplasia (LGD) or high-grade dysplasia (HGD), regular follow-up is required after resection of the lesions for the possibility of recurrence after five years and development of pancreatic ductal adenocarcinoma (PDAC) in the pancreas," he said.

IPMNs are precancerous lesions of the pancreas, and several studies have sought to identify risk factors to support decisions regarding which patients should undergo surgical resection. Little is known, however, about the course of patients who undergo resection.

Dr. Kim and colleagues used data from 577 consecutive patients who underwent surgery for IPMN to evaluate factors associated with recurrence and prognosis according to pathology and margin status.

Among the 548 patients included in the analysis, 353 had LGD, 78 had HGD, and 117 had invasive IPMN pathology.

After a median follow-up of 56 months, 50 patients (9.1%) developed recurrences, including six patients (1.7%) with LGD, four patients (5.1%) with HGD and 40 patients (34.2%) with invasive IPMN, the researchers report in Annals of Surgery.

Recurrence rates were higher among patients with positive margins than among patients with R0 resection, regardless of pathology.

Cumulative recurrence rates at five years were significantly higher in patients with invasive IPMN (37.6%) than in patients with LGD (0.7%) or HGD (4.3%), and recurrence risk increased continuously even after five years from resection in all three groups.

In multivariate analysis, invasive IPMN pathology was associated with an 18-fold increased risk of recurrence, and malignant margin was associated with a 2.6-fold increased risk of recurrence. Elevated CA19-9 was also associated with a significant 2.5-fold increased risk of recurrence.

Five-year survival rates were significantly worse among patients with invasive IPMN (48%) than among those with LGD (89%) or HGD (84%) and among patients with malignant margins (31%) than those with LGD margins (83%) or negative margins (81%).

Malignant margin, N1 stage, venous invasion, chemotherapy, and elevated CA19-9 were independent predictors of worse disease-free survival.

Among the 431 patients with noninvasive IPMN, four developed extrapancreatic recurrences: two patients who received supportive care due to poor general conditions and one who received chemotherapy died within several months; one patient with local recurrence of a mass around the superior mesenteric vein underwent excision and remained alive.

"According to the American Gastroenterological Association guidelines for the management of IPMN, surveillance of pancreatic cysts can be discontinued if there has been no significant change after 5 years, and surveillance of pancreatic cysts without high-grade dysplasia or invasive IPMN at surgical resection is extremely unlikely to be cost-effective," Dr. Kim said.

"However, results of our study indicate that even patients with low-grade dysplasia or high-grade dysplasia should undergo lifelong postoperative surveillance for any possibility of disease recurrence or development of a new pancreatic cancer, consistent with European guidelines on IPMN, which also recommend lifelong surveillance following resection."

He added, "Invasive IPMN developed more recurrences and had worse survival than low-grade dysplasia or high-grade dysplasia, indicating the need for more efficient postoperative treatment strategies including the novel adjuvant chemotherapy regimen for invasive IPMN."

"Malignant margins, which included margins with high-grade dysplasia and invasive IPMN, were associated with a higher cumulative risk of recurrence and worse prognosis. This margin status, therefore, needs additional resection to achieve negative, or at least low-grade dysplasia, margin status to guarantee better survival and recurrence outcomes," Dr. Kim said. "Otherwise, postoperative concurrent chemoradiotherapy should be considered for local control of the disease."

SOURCE: https://bit.ly/2S0fs0s Annals of Surgery, online September 15, 2020.

MAMMAPRINT FOR ILC?

The MammaPrint 70-gene signature has similar prognostic performance in women with early-stage invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) and may help guide chemotherapy decisions, according to an exploratory analysis of the MINDACT trial reported at the 12th European Breast Cancer Conference.

ILC is enriched with features indicating low proliferative activity, noted investigator Otto Metzger, MD, of the Dana Farber Cancer Institute in Boston.

"Data from retrospective series have indicated no benefit with adjuvant chemotherapy for patients diagnosed with early-stage ILC," he said. "It's fair to say that chemotherapy decisions for patients with ILC remain controversial."

With this in mind, Metzger and colleagues analyzed data for 5,313 women who underwent surgery for early-stage breast cancer (node-negative or up to three positive lymph nodes) and were risk-stratified to receive or skip adjuvant chemotherapy based on both clinical risk and the MammaPrint score for genomic risk. Fully 44% of women with ILC had discordant clinical and genomic risks.

With a median follow-up of 8.7 years, the 5-year rate of distant metastasis–free survival among all patients classified as genomic high risk was 92.1% in women with IDC and 88.1% in women with ILC, with overlapping 95% confidence intervals. Rates of distant metastasis–free survival for patients with genomic low risk were 96.4% in women with IDC and 96.6% in women with ILC, again with confidence intervals that overlapped.

The pattern was essentially the same for overall survival, and results carried over into 8-year outcomes as well.

"We believe that MammaPrint is a clinically useful test for patients diagnosed with ILC," Metzger said. "There are similar survival outcomes for ILC and IDC when matched by genomic risk. This is an important message."

It should be standard to omit chemotherapy for patients who have ILC classified as high clinical risk but low genomic risk by MammaPrint, Metzger recommended. "By contrast, MammaPrint should facilitate chemotherapy treatment decisions for patients diagnosed with ILC and high-risk MammaPrint," he said.

Prognostic, but Predictive?

"This is a well-designed prospective multicenter trial and provides the best evidence to date that MammaPrint is an important prognostic tool for ILC," Todd Tuttle, MD, of University of Minnesota in Minneapolis, said in an interview.

Tuttle said he mainly uses the MammaPrint test and the OncoType 21-gene recurrence score to estimate prognosis for his patients with ILC.

These new data establish that MammaPrint is prognostic in ILC, but the value of MammaPrint's genomic high risk result for making the decision about chemotherapy is still unclear, according to Tuttle.

"I don't think we know whether MammaPrint can predict the benefit of chemotherapy for patients with stage I or II ILC," he elaborated. "We need further high-quality studies such as this one to determine the best treatment strategies for ILC, which is a difficult breast cancer."

Study Details

Of the 5,313 patients studied, 487 had ILC (255 classic and 232 variant) and 4,826 had IDC according to central pathology assessment, Metzger reported.

MammaPrint classified 39% of the IDC group and 16% of the ILC group (10% of those with classic disease and 23% of those with variant disease) as genomically high risk for recurrence. The Adjuvant! Online tool classified 48.3% of ILC and 51.5% of IDC patients as clinically high risk.

Among the 44% of women with ILC having discordant genomic and clinical risk, discordance was usually due to the combination of low genomic risk and high clinical risk, seen in 38%.

The curves for 5-year distant metastasis–free survival stratified by genomic risk essentially overlapped for the IDC and ILC groups. Furthermore, there was no significant interaction of histologic type and genomic risk on this outcome (P = .547).

The 5-year rate of overall survival among women with genomic high risk was 95.6% in the IDC group and 93.5% in the ILC group. Among women with genomic low risk, 5-year overall survival was 98.1% in the IDC group and 97.7% in the ILC group, again with overlapping confidence intervals within each risk category.

The study was funded with support from the Breast Cancer Research Foundation. Metzger disclosed consulting fees from AbbVie, Genentech, Roche, and Pfizer. Tuttle disclosed no conflicts of interest.

SOURCE: Metzger O et al. EBCC-12 Virtual Conference. Abstract 6.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

AVASTIN FOR OVRAIAN STROMAL TUMORS?

In the phase II ALIENOR trial reported in JAMA OncologyIsabelle Ray-Coquard, MD, and colleagues found that the addition of bevacizumab to paclitaxel did not improve the 6-month progression-free rate among women with relapsed ovarian sex cord–stromal tumors.

Isabelle Ray-Coquard, MD

Isabelle Ray-Coquard, MD

Study Details

The study, performed in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup, included 60 women with sex cord–stromal tumors that had relapsed after at least one platinum-based chemotherapy from sites in France, Germany, Italy, Japan, and Belgium. Patients were randomly assigned to receive:

  • Paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks alone for six cycles (n = 32)
  • Paclitaxel with bevacizumab at 10 mg/kg on days 1 and 15 every 4 weeks for six cycles followed by maintenance bevacizumab (15 mg/kg every 3 weeks) for up to 1 year or until progression or unacceptable toxicity (n = 28).

Crossover to bevacizumab was permitted after progression during or following paclitaxel alone.

The primary outcome measure was 6-month progression-free rate. The trial used an adaptive Bayesian design, in which the combination group would be superior to the paclitaxel group if the probability of superiority was ≥ 90% at final analysis. Enrollment occurred between 2013 to 2016 and the final analysis database lock was in March 2020.

Six-Month Progression-Free Rate

Median follow-up was 38.9 months.

The estimated 6-month progression-free rate was 71% (95% credible interval = 55%–84%) with paclitaxel alone and 72% (95% credible interval = 55%–87%) with paclitaxel/bevacizumab. The Bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination was 57%, which was less than the predefined superiority threshold.

The objective response rate was 25% with paclitaxel alone vs 44% with the combination, with median response durations of 18.0 months vs 15.9 months. Median progression-free survival was 14.7 months vs 14.9 months, with Kaplan-Meier estimated 6-month rates of 72% vs 78%. Kaplan-Meier estimates of overall survival were 94% vs 93% at 1 year and 87% vs 73% at 2 years.

KEY POINTS

  • The addition of bevacizumab to paclitaxel did not improve the 6-month progression-free rate.
  • The estimated 6-month progression-free rate was 71% with paclitaxel and 72% with paclitaxel/bevacizumab.

Among the 16 patients who crossed over to bevacizumab after progression, median progression-free survival from start of bevacizumab was 6.9 months, with 3 patients having responses of ≥ 12 months.

Adverse Events

The most common adverse events of any grade were hypertension, fatigue, and neuropathy, with bleeding and proteinuria being more common in the combination group. The most common grade ≥ 3 adverse events were hypertension, infection, and neutropenia. No gastrointestinal perforations were observed. Adverse events led to discontinuation of treatment within 6 months in one patient in the combination group.

The investigators concluded, “Weekly paclitaxel is a new option for relapsed sex cord–stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord–stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit…. To our knowledge, this is the first randomized trial in sex cord–stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting.”

Dr. Ray-Coquard, of Centre Léon Bérard, Université Claude Bernard Lyon, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by Roche. For full disclosures of the study authors, visit jamanetwork.com.

PATIENTS CAN READ THEIR CLINICAL NOTES

Starting November 2, all patients in the United States will have immediate access to clinical notes and thus will be able to read their doctors' writings, as well as test results and reports from pathology and imaging.

The 21st Century Cures Act mandates that patients have fast, electronic access to the following types of notes: consultations, discharge summaries, history, physical examination findings, imaging narratives, laboratory and pathology report narratives, and procedure and progress notes.

But this federal mandate, called "open notes" by many, is potentially confusing and frightening for patients, say some physicians. Others worry that the change will increase workload as clinicians tailor notes for patients and answer related questions.

The law means that inpatient and outpatient notes will be released immediately and that patients will have immediate access to testing and imaging results, including results from sexually transmitted disease tests, Pap tests, cancer biopsies, CT and PET scans, fetal ultrasounds, pneumonia cultures, and mammograms.

Such notes could contain sensitive information, and there is concern that patients could be shocked, confused, or annoyed by what they read, even with more run-of-the-mill notes.

Champions of open notes say that the benefits, including better provider-patient communication, greatly outweigh such risks.


Dr Charlotte Blease

"This is about convenience — a bit like online banking," comments Charlotte Blease, PhD, resident scholar at OpenNotes, an advocacy nonprofit organization headquartered at the Beth Israel–Deaconess Medical Center in Boston, Massachusetts. "But it's a culture shift for doctors," she tells Medscape Medical News.

"It turns physician paternalism on its head," says C. T. Lin, MD, chief medical information officer, UCHealth, Denver, Colorado. The change requires "some letting go of old traditions" in medicine, he writes in an August blog post, referring to the fact that a computer screen — and not a physician — may tell patients about a new health problem.

Lin summarizes the experience at the University of Colorado Cancer Center, which has allowed patients to have access to oncology notes for the past 5 years: "No issues and highly appreciated by patients. We have nothing to fear but fear itself."

A New Audience

Other institutions have also been voluntarily implementing open notes.

UC Davis Health in Sacramento, California, has run an optional program for the past year. However, only about two dozen of approximately 1000 staff physicians opted in to the program.


Dr Scott MacDonald

"This illustrates the point that it's a new thing that physicians aren't used to doing. They've traditionally written notes for the benefit of their colleagues, for billing, for their own reference," says Scott MacDonald, MD, an internist and electronic health record medical director at UC Davis Health, tells Medscape Medical News.

"They've never ― until recently ― had the patient as one of the audiences for a note," he says.

Liam Keating, MD, an otolaryngologist in Martinez, California, recalls that he once wrote "globus hystericus," and the patient wanted to sue him for saying that the patient was hysterical. "I now just code 'Globus' (if I don't jump straight to LPD [lateral pharyngeal diverticulum])," he commented in response to a Medscape commentary on open notes.

Sensitive information occurs more often in certain specialities, for example, psychiatry, genetics, adolescent medicine, and oncology, say experts.

"Cancer is an area that is highly charged for patients and doctors alike," MacDonald points out. When reading pathology or imaging notes, patients may learn that they have been diagnosed with cancer or that they have a recurrence "without the physician being able to contextualize it and explain things — that's just new and scary," he says.

California law dictates that providers cannot post cancer test results without talking with the patient first, says MacDonald, but not all states have such laws.

Adjustments Needed, or Not, With Open Notes

At UCHealth in Aurora, Colorado, Robert Breeze, MD, vice-chair of neurosurgery, says he has adjusted his practice to accommodate open notes and to anticipate trouble spots.

"When I order imaging or send pathology specimens, I have already discussed with the patient the possibilities, including cancer, and what we will do next. Patients deeply appreciate these discussions, before they see the results," he comments in an institutional white paper issued in anticipation of the changes on November 2.

This is called precounseling, says Trent Rosenbloom, MD, MPH, director of patient portals at Vanderbilt University Medical Center, Nashville, Tennessee, which has been a pioneer in information sharing with patients. Their system does delay the release of information in the case of "complicated" results, such as from cancer biopsies, he tells Medscape Medical News.

However, Christiaan Hoff, MD, PhD, a surgeon at the Medical Center Leeuwarden, the Netherlands, wonders how important it is for the physician to be present when the patient receives bad news, including news about cancer. "We may overestimate our added value in these situations," he suggests.

"Our empathy may not outweigh" the disadvantages of the situation, and the "finer points of our explanation will often go unnoticed" by the stressed patient, he comments. Hoff was also responding to the Medscape commentary about open notes.

In that commentary, Jack West, MD, a medical oncologist at City of Hope Cancer Center, Duarte, California, was concerned about misunderstandings. Oncology is complex, and patients can struggle to understand their prognosis and planned treatment efficacy, especially in cases of metastatic disease, he wrote.

This concern is somewhat refuted by a study published October 5 in Cancer Cell. Responses to two surveys involving 96 oncology clinicians at three US centers found that almost half (44%) believed that their patients "would be confused" by open notes.

However, only 4% of the 3418 cancer patients from the same surveys reported being confused by open notes. (A majority of participants had more than a high school education, and English was their primary language.)

"Patient and clinician views about open notes in oncology are not aligned, with patients expressing considerably more enthusiasm," write the authors, led by Liz Salmi, senior strategist at OpenNotes, who has been treated for brain cancer.

"All clinicians are anxious at first," Salmi tells Medscape Medical News. "Those patients who have more serious or chronic conditions...are more likely to read their notes."

The survey results echo the early experience reported from Sweden, where open notes was launched in 2012. "Patients have loved it from the beginning," says Maria Haggland, PhD, of Uppsala MedTech Science Innovation Center.

However, when the scheme first launched, it was considered to be "very controversial," and "there were a lot of complaints, from health care professionals, especially," she adds.

Over time, clinicians have embraced open notes, and the program has 7.2 million patient accounts in a country of 10 million people, she observed during an October 5 webinar on open notes.

More Work for Already Overworked Clinicians?

An outstanding concern about open notes is that it will cause more work for healthcare professionals.

Traditionally, doctors have written notes using medical lexicon, including a lot of abbreviations and jargon for efficiency's sake. Now that patients will read the notes, will clinicians have to spell out things in lay terms, alter their writing so as not to offend, and generally do more work?

William Harvey, MD, chief medical information officer, Tufts Medical Center, Boston, acknowledged that that may be the case.

In a forthcoming note to staff about the November 2 start of open notes, Harvey will include a reminder to accommodate the patient as a reader. But that may or may not mean an increase in work volume, depending on the provider. "Clinical note writing is highly personal. There's an art to it," he tells Medscape Medical News. "So it's hard to give standard advice."

Steven Reidbord, MD, a psychiatrist in private practice in San Francisco and a lecturer at California Pacific Medical Center, is particularly concerned about the impact of open notes on progress notes, which he calls a tool to develop strategies and make observations while working with a patient.

By watering down the language for patients, "you are trading away the technical precision and other advantages of having a professional language," he tells Medscape Medical News.

"These notes serve many masters already," he says, referring to purposes such as utilization review and billing. "The more masters they serve, the less useful they are to get medical work done."

Medical information officer MacDonald says the new law doesn't mandate a change in writing style.

In a study published last year, researchers analyzed notes written by oncologists before and after adoption of open notes. They found that on average, clinicians did not change their note writing. The investigators analyzed more than 100,000 clinical notes written by 35 oncologists at a single center.

Advocates for open notes emphasize that there are benefits for clinicians.

"Doctors are overworked. They're overburdened. But empowered patients can help the doctor," says OpenNotes' Blease. She cites survey data that show that patients better understand their treatment plan and medication, which can cut down on physician workload.

Open notes are "what you make of it," says Marlene Millen, MD, an internist at UC San Diego Health, which has had a pilot program for 3 years. Each day, Millen discusses a shared note with two or three patients. "I actually end all of my appointments with, 'Don't forget to read your note later,' " she tells Medscape Medical News.

"I was a little afraid of this initially," she says, but within the first 3 months of the pilot, about 15 patients gave her direct feedback on how much they appreciated her notes. "It seemed to really reassure them that they were getting good care."

The persons quoted in this article have disclosed no relevant financial relationships.

Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay and MedPageToday and had bylines in WashingtonPost.com, MSNBC, and Yahoo. Email: nmulcahy@medscape.net and on Twitter: @MulcahyNick.

STROKE RISK AFTER TIA REMAINS HIGH

The incidence of stroke following a transient ischemic attack (TIA) has decreased somewhat over the past 50 years but hardly at all during the past decade, a new meta-analysis shows.

"This systematic review and meta-analysis found that transient ischemic attack continues to be associated with a high risk of early stroke. However, the rate of post-TIA stroke might have decreased slightly during the past 2 decades," the authors conclude.

Dr Ramin Zand

"In recent years, there has been a lot of advancement in the treatment of stroke but not so much improvement for TIA," senior author Ramin Zand, MD, Geisinger Neuroscience Institute, Danville, Pennsylvania, told Medscape Medical News.

"Many strokes happen in the first few days after a TIA, so it is of utmost importance to evaluate these patients quickly and get preventative treatments on board as soon as possible. Unfortunately, this does not always happen," he said.

"Speedy diagnosis and treatment of TIA is possibly even more important than for stroke, as no brain damage has yet occurred in TIA patients and we have the opportunity to stop such damage from occurring," Zand added.

The meta-analysis of all published studies of TIA outcomes from 1971 to 2019 was published online in JAMA Neurology on October 12. A total of 68 studies involving 206,455 patients were included.

The rate of subsequent ischemic stroke after TIA over the whole time span was estimated to be 2.4% within 2 days, 3.8% within 7 days, 4.1% within 30 days, and 4.7% within 90 days.

The authors evaluated the population with respect to three periods ― before 1999 (group A), from 1999 to 2007 (group B), and after 2007 (group C). These periods were chosen on the basis of changes to the guidelines on TIA made in 1999 and two important publications on TIA in 2007.

Results showed that there was a significant reduction in stroke following TIA after the change in the guidelines in 1999.

For the 2 days after TIA, stroke rates fell from 3.4% in group A (before 1999) to 2.1% in groups B and C.

Similarly, stroke rates within 7 days of TIA went from 5.5% before 1999 to 3.2% during the period 1999–2007 and to 2.9% after 2007.

For the period within 30 days of a TIA, stroke rates dropped from 6.3% pre-1999 to 3.4% in 1999–2207 and 2.9% after 2007.

Within 90 days of TIA, stroke rates were 7.4% pre-1999 and 3.9% in both 1999–2007 and after 2007.

Zand explained that some changes were made to the guidelines regarding TIA treatment in 1999, and in 2007, a couple of landmark publications on risk for stroke following TIA appeared.

"We thought these may have had an effect on subsequent stroke rates by raising awareness," he added.

"In 1999, after the guidelines changed, we did see a reduction in stroke after TIA," he said.

They were hoping to see another reduction after the publication of the landmark studies, which confirmed the high risk for stroke after TIA and the need for urgent management of the condition. "And because the system of care for stroke is improving, we thought this may also be the case for TIA," he noted. "But although rates reduced a little after 1999, they have since stabilized with no further improvement after 2007."

Zand suggested several reasons for this finding, including the fact that many people are not aware of the symptoms of TIA and that TIA should be regarded with the same urgency as stroke.

"There is a large variation in the treatment of suspected TIA ― some centers treat this as a medical emergency and admit patients with suspected TIA to hospital, while others do not approach TIA as an urgent situation. And although there has been a lot of public education related to stroke in recent years, this has not extended to TIA," he explained.

"Many clinicians may also not give the same level of importance to a suspected TIA as to a suspected stroke," he said.

Another problem is the lack of a good imaging biomarker for TIA and the many other conditions that mimic TIA, making a definite diagnosis difficult. "The TIA diagnosis is based on taking a thorough history and identifying TIA risk factors, whereas for stroke, we can see a clear deficit on imaging," Zand said.

"Our study included patients who had a diagnosis of TIA. As many TIA patients are not diagnosed, the actual incidence of stroke following a TIA is probably quite a bit higher than we reported," he added.

Zand called for better public education to raise awareness of TIA with the message to seek medical help quickly. "Symptoms of TIA are similar to stroke and include weakness, sensory changes, and visual deficits, but as these are transient and often resolve after a few minutes or hours, many people do not seek assistance. But they should go to ER urgently," he emphasized.

He also highlighted the need to improve the diagnosis and risk stratification of TIA for patients who do present with these symptoms or who have recently had these symptoms, with timely medical attention and intensive evaluation either in a hospital or in a TIA clinic.

JAMA Neurol. Published online October 12, 2020. Abstract

ICOTINIB+RT FOR ESOPHAGEAL CANCER

NEW YORK (Reuters Health) - Icotinib with concurrent radiotherapy (RT) boosts survival and may have other benefits compared to RT alone in elderly patients with unresectable esophageal squamous cell carcinoma, according to Chinese researchers.

Dr. Shixiu Wu told Reuters Health by email, "I think our trial is the first involving the combination of targeted therapy and RT in old people with esophageal cancer and we demonstrated that it improved the overall survival with less toxicity."

In a paper in JAMA Network Open, Dr. Wu of the Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, and colleagues say their essential hypothesis was that the combination "would promote local and regional effects as well as diminish distant metastases."

They note that in preclinical studies, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor icotinib has markedly inhibited proliferation of human epidermoid squamous carcinoma cell lines with a high level of EGFR.

To investigate further, the researchers conducted a multicenter, open-label trial involving 127 patients aged 70 or older with advanced unresectable esophageal squamous cell carcinoma, all of whom were prescribed RT at 60 Gy in 30 fractions. Participants were randomly assigned to receive or not receive icotinib, 125 mg t.i.d.

After a median follow-up of 42.8 months, the overall response rate was 84.4% in the intervention group and 60.3% in the control group. The median overall survival (OS) was 24.0 months with RT plus icotinib and 16.3 months with RT alone.

No between-group differences were seen in grade 3 or 4 adverse events and toxic effects were well controlled with appropriate dose reductions and supportive care.

In the RT plus icotinib group, median overall survival was not reached among patients with EGFR overexpression; it was 16.3 months in those with low EGFR expression.

Thus, concluded Dr. Wu, patients with higher EGFR expression benefit from the addition of icotinib, "which suggests precise targeting of EGFR-driven esophageal squamous cell carcinoma should remain an important therapeutic aim despite the recent focus on immune checkpoint inhibitors application in esophageal cancer. That may extend to other types of cancer."

SOURCE: https://bit.ly/3lELPyy JAMA Network Open, online October 7, 2020.

NO CHEMO OPTION FOR ALL

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, up-front chemo-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, "impressive" survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, "60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab," lead researcher Robin Foà, MD, from Sapienza University of Rome, in Italy, told Medscape Medical News.

"The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity," Foà added.

"I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age," Foà said.

The results of the study were published October 22 in The New England Journal of Medicine.

"Innovative" and "Highly Successful"

This "innovative" chemo-free approach proved "highly successful" with "surprisingly" few toxic effects, writes Dieter Hoelzer, MD, PhD, University of Frankfurt, Germany, in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24 – 82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 μg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab — to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival (DFS) was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2BPAX5, or both [ie, IKZF1plus]).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients, neutropenia in four patients, persistent fever in two patients, and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is "remarkable," Hoelzer writes in his editorial. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant — "a consequence that is avoided with targeted therapy."

Unanswered Questions

"Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment," editorialist Hoelzer notes.

He says other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

"If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials," Hoelzer concludes.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome. Disclosures for the authors and the editorialist are available with the full article at NEJM.org.

N Engl J Med. Published October 22, 2020. Abstract, Editorial