Publications Update # 29

Publications Update # 29
An Unknown farm southwest of Ann Arbor, MI; Photograph by Shitanshu Uppal

Non-Medical Article of the Week

Unlearning Anxiety

On this Ezra Klein Show, neuroscientist Jud Brewer, author of "Unwinding Anxiety," describes anxiety as a learned habit. He breaks down the habit loop into three stages: trigger (like a stressful thought), behavior (such as worrying), and reward (relief from the behavior). This loop can become self-reinforcing, making anxiety a tough cycle to break. To disrupt it, Brewer suggests:

  1. Recognizing your triggers.
  2. Practicing mindfulness to observe thoughts and feelings.
  3. Questioning and reframing negative thoughts.
  4. Employing healthy coping methods like exercise or relaxation.
  5. Prioritizing self-compassion.

Brewer believes that understanding anxiety as a habit allows us to unlearn and combat it, leading to more fulfilling lives.

You can buy the book by searching for - Unwinding Anxiety by Judson Brewer

Ovarian Cancer

HIPEC in Ovarian Cancer

OVHIPEC study was published in 2018. Since then, the NCCN guidelines have added a footnote with the following text.

Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin (100 mg/m2 ) can be considered at the time of IDS for stage III disease.

Two papers published this week further support the routine use of HIPEC in interval debulking surgery:

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial - PubMed
Dutch Cancer Foundation (KWF Kankerbestrijding).

A 10-year final survival analysis of the original OVHIPEC study shows an overall survival benefit of 1 year (median OS 33·3 months vs. 44·9 months; p=0·011)

A second randomized controlled trial now shows the benefit of HIPEC in ovarian cancer patients undergoing interval debulking surgery.

Hyperthermic Intraperitoneal Chemotherapy After Interval Cytoreductive Surgery for Patients With Advanced-Stage Ovarian Cancer Who Had Received Neoadjuvant Chemotherapy - PubMed
This study suggests that ICS in conjunction with HIPEC was associated with longer PFS and OS than ICS without HIPEC for patients with advanced-stage ovarian cancer and was not associated with higher rates of postoperative complications. The lower rate of peritoneal recurrence after HIPEC may be asso…

In this study, 109 patients underwent HIPEC compared to 87 without HIPEC during interval debulking surgery. The median PFS was 23 months in the HIPEC group vs. 14 months (p = 0.05). Overall survival data are not mature completely (HIPEC median OS not reached vs. 53 months).

How does HIPEC improve OS in ovarian cancer?

Critiques have questioned why HIPEC yields a larger OS benefit despite only a modest improvement in PFS. The pattern of recurrence answers this question. In this study (Table 3) - patients with HIPEC had a much lower rate of intraperitoneal recurrence compared to those without HIPEC (32% vs. 64%) and much higher lymph node metastasis (46% vs. 25%). Intraperitoneal recurrences can easily become life-threatening if the bowel is compromised, while patients with visceral or lymphatic recurrences often keep tolerating therapies for recurrence.

We need to consider repeating the LIONS trial (lymphadenectomy vs. no lymphadenectomy) in patients undergoing interval debulking surgery with HIPEC in both arms. 

How do we encourage people to consider using HIPEC?

Unfortunately, I can no longer find the tweet to give appropriate attribution but someone on twitter (sorry X) suggested - call it HIPECOMAB and the utilization will skyrocket. If you find this tweet, let me know, I will add it to this post :)

Immunotherapy in Ovarian Cancer

Two recent trials in ovarian cancer explored the role of atezolizumab in newly diagnosed ovarian cancer. The first trial - IMagyn050/GOG 3015/ENGOT-OV39, published in 2021. This trial showed no benefit of adding immune checkpoint inhibitors to the combination of chemotherapy (Carboplatin/Taxol) and Bevacizumab (median PFS 20.8 versus 18.5 months, p = n.s).

Atezolizumab, Bevacizumab, and Chemotherapy for Newly Diagnosed Stage III or IV Ovarian Cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39) - PubMed
Current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed OC. Insight from this trial should inform further evaluation of immunotherapy in OC.

This week, the results from ATALANTE/ENGOT-ov29 trial were published. This trial used the same combination in recurrent platinum-sensitive ovarian cancer. The results were similar to the IMagyn050 trial. Adding immune checkpoint inhibitors does not improve survival in ovarian cancer.

Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial - PubMed
ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1-positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC.
Immune checkpoint inhibitors are worthless in ovarian cancer.

Ongoing studies are being conducted to identify more effective ways of using immunotherapy for a subset of patients. However, traditional measures of success, such as PD-L1 receptor status and tumor mutational burden, have not been able to predict the response to immunotherapy in HGSOC patients.

Endometrial Cancer

Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 “Lynch-like” mismatch repair gene mutation - PubMed
Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expressi…

Just read this paper for now; more on this topic next week !!