Since older patients with diffuse large B-cell lymphoma (DLBCL) are known to have an increased risk of treatment-related morbidity and mortality, researchers conducted a retrospective study to quantify this risk and identify the factors associated with mortality and serious morbidity during the first cycle of immunochemotherapy.

Adam Olszewski, MD, an assistant professor at Brown University, and coauthors noted that 1 in 45 older patients treated with immunochemotherapy for their DLBCL die during the first month of treatment, and 25% are hospitalized. Thus, knowing the risk factors for this mortality and morbidity offers an opportunity to improve preventive interventions, including identifying patients who would benefit from granulocyte colony-stimulating factor (G-CSF).

Patients for this study were chosen from the Surveillance, Epidemiology and End Results (SEER) registry if they were at least 65 years of age and had Medicare claims, a diagnosis of DLBCL between 2003 and 2011, and received rituximab-based immunochemotherapy. The therapy was defined as 

, consisting of rituximab, cyclophosphamide, and vincristine in combination with doxorubicin, mitoxantrone, or etoposide.

Risk factors for death and hospitalization within the first 30 days (early mortality) of treatment were analyzed using multivariable logistic regression models. G-CSF use was also assessed.

A total of 5530 patients were analyzed; they had a median age of 76 years, and 94% had received R-CHOP—like regimens containing doxorubicin. The cumulative incidence of early mortality was 2.2%.

Characteristics associated with an increased risk of early mortality were age ≥75, lymphoma-related symptoms (B symptoms), chronic kidney disease, poor performance status, use of mobility aids, hospitalization within the past year, and upper endoscopy within the past year.

Patients with ≤1 of these risk factors had a low risk of early mortality (0.6%), whereas those with ≥4 risk factors had a risk of 8.3%. In the high-risk group, this was mitigated by receipt of G-CSF, which lowered the early mortality risk 3-fold. However, only 66% of patients in this study received G-CSF during the first cycle. The cumulative incidence of hospitalization in the first 30 days was 23.5%, with the highest frequency occurring at day 8.

In addition to quantifying early mortality risk, the study also highlighted the importance of G-CSF use in this elderly population, and demonstrated that this intervention may be underused. The information gained from this study could be used not only to stratify risk but also to improve outcomes in this patient population.

 Olszewski AJ, Mantripragada KC, Castillo JJ. Risk factors for early death after rituximab-based immunochemotherapy in older patients with diffuse large B-cell lymphoma. 

Articles

Older patients with diffuse large B-cell lymphoma (DLBCL) often have an increased risk of treatment-related morbidity and mortality, but the use of preventive interventions, such as granulocyte colony-stimulating factor (G-CSF) may help. 

G-CSF Underused in Older Patients Receiving Immunochemotherapy for DLBCL

Immune-related adverse events (irAEs) have become a well-recognized group of AEs associated with immune checkpoint inhibitors. They can be difficult to identify and manage because they are different from toxicities typically seen with classic cytotoxic mechanisms.

The endocrine system, along with skin and the gastrointestinal system, is commonly affected by these irAEs. Importantly, some of these endocrine irAEs can be life threatening. Researchers in Spain recently published a review of the most common endocrine irAEs and their management strategies.

Hypophysitis is a grade 3/4 irAE most frequently associated with ipilimumab (Yervoy) in which it can occur at an incidence up to 17%. With PD-1 and PD-L1 inhibitors, hypophysitis is less common, with an incidence of <2%.

Hypophysitis symptoms are derived from the swelling of the pituitary gland and from hormonal deficiencies. The symptoms include headache, asthenia, fatigue, nausea, weakness, lethargy, erectile dysfunction, and loss of libido. The median time to onset of hypophysitis is 11 weeks.

If hypophysitis is suspected, immune checkpoint inhibitors should be withheld and both pituitary hormones and target tissue hormones should be measured. To treat hypophysitis, high-dose glucocorticoids are used with a slow tapering to avoid relapse or an adrenal crisis. Once the steroids are tapered, hormone replacement therapy is necessary if a deficiency is present.

The development of hypophysitis does not imply discontinuation of cancer treatment, and once the corticosteroid dose has been reduced, treatment with checkpoint inhibitors may be resumed.

Thyroid disorders are caused by immune checkpoint inhibitors and occur most frequently as hypothyroidism and hyperthyroidism. Most thyroid dysfunctions are not extreme or life-threatening and anticancer treatment can continue. However, thyroiditis can also occur. In patients with cancer, it may be difficult to recognize thyroid disorders as their symptoms can be mistakenly attributed to the cancer itself, or other medications.

 include asthenia, constipation, dry skin, hair loss, and weight gain, and treatment typically involves daily levothyroxine.

 often presents with palpitations, increased stool frequency, heat intolerance, sweating, and weight loss. There are often diagnostic and management difficulties when dealing with hyperthyroidism. Because of this, clinicians are encouraged to consult with an endocrinologist to diagnose and manage this disorder.

Primary adrenal insufficiency is uncommon but can occur in up to 4% of patients treated with an immune checkpoint inhibitor.

Symptoms stem from lack of glucocorticoids and mineralocorticoids and are often nonspecific, such as nausea, weakness, fatigue, anorexia, abdominal pain, and weight loss.

Treatment of primary adrenal insufficiency (and secondary adrenal insufficiency) is based on replacing glucocorticoids. Most often, this includes oral hydrocortisone which aims to mimic the physiological circasian rhythm.

In the acute form, adrenal insufficiency can progress to adrenal crisis. Adrenal crisis commonly presents with hypovolemic shock, abdominal pain, fever, and nonspecific symptoms such as nausea, vomiting, lethargy, confusion or coma. This requires urgent treatment with hydrocortisone, even before test results can confirm the diagnosis. It is also highly recommended that an endocrinologist is consulted for acute management, differential diagnosis and evaluation for long-term replacement needs.

In cases of adrenal insufficiency, adrenal crisis can be avoided by patient education. Patients should learn the most important concepts: how to increase the steroid dose during illness or a medical procedure, the need to obtain medical assistance if they are unable to take oral medication, and the importance of wearing a medical alert necklace or bracelet. Hydrocortisone emergency injections must be provided to patients and their families, along with proper instruction on how and when to administer them.

Patients taking immune checkpoint inhibitors may also develop other, less common endocrinopathies, such as Graves ophthalmopathy, adrenal crisis, and autoimmune diabetes.

As a class, endocrine irAEs must be carefully documented and managed, as some conditions can be life threatening or become life threatening. In most cases, however, proper management of these conditions allows continuation of immunotherapy.

González-Rodríguez E, Rodríguez-Abreu D, Spanish Group for Cancer Immuno-Biotherapy (GETICA). Immune checkpoint inhibitors: review and management of endocrine adverse events. 

Some immune-related adverse events (irAEs) can be life threatening. Researchers in Spain recently published a review of the most common endocrine irAEs and their management strategies.

Identifying and Managing Endocrinopathies With Immune Checkpoint Inhibitors

Following publication in 1990 of the National Institutes of Health (NIH) consensus statement recommending breast-conservation surgery as the preferred surgical treatment for the majority of women with stage I and stage II breast cancer,

 several studies have confirmed similar long-term survival rates of breast-conservation therapy compared with mastectomy 18 to 20 years postoperatively, although these studies present conflicting results as to whether breast-conservation therapy is associated with increased local relapse rates.

The results of this collective research and the NIH Consensus Statement led to a steady decline in mastectomy rates in the United States for women with stage I or stage II disease receiving surgery

—from a 1988 pre-consensus statement rate of 77%, to a rate of 38% in 2004.

 National databases, such as Surveillance, Epidemiology, and End Results (SEER), can provide an overall picture of mastectomy procedures performed in the United States. The most recent publication of mastectomy rates from the SEER database presents data through 2008 for women with T1-2 N0-3 M0 tumors who had surgery (either breast-conservation surgery or mastectomy).

 Mastectomy rates steadily decreased from 2001 to 2005, from a high of 40.2% to a nadir of 35.6%. Following this, mastectomy rates began to rise from 2005 through 2008, back up to 38.4%, the highest rate since 2002.

A publication of mastectomy rates from the European Society of Breast Cancer Specialists suggests that this trend observed here is distinct from trends in mastectomy rates in Europe.

 In this study, mastectomy rates were analyzed from 2003 to 2010 from >15,000 women throughout Italy, Belgium, Germany, and Switzerland who underwent surgery for early-stage disease. Investigators reported that rates steadily declined from a high of 29.9% in 2005 to only 18.6% in 2010.

Is the Mastectomy Rate Among US Women Too High?

		The 30th Annual Miami Breast Cancer Conference ® (MBCC) featured clinical perspectives on this question from Patrick I. Borgen, MD, chair, Department of Surgery, and director, Maimonides Breast Cancer Center, at the Maimondes Medical Center, Brooklyn, New York, and J. Michael Dixon, MD, professor of Breast Surgery at the University of Edinburgh, Scotland, and consultant breast surgeon at Western General Hospital. Below are excerpts from their presentations and from video interviews with 

There are both desirable and undesirable explanations for an increasing mastectomy rate. Examples of positive reasons include improvements in the radiographic identification of occult lesions and an increase in the identification of genetic risk factors for aggressive disease (eg, BRCA mutations). Undesirable reasons for increasing mastectomy rates include an unsubstantiated worry about recurrence, an overestimation of the survival benefit of mastectomy, and a general lack of knowledge about the available surgical choices. Additional reasons include improved postmastectomy reconstructive outcomes and a desire to avoid the side effects of adjuvant radiation therapy.

Another crucial factor in judging the significance of an increasing mastectomy rate is the distinction between mastectomy performed therapeutically on the primary tumor and that performed on the contralateral breast as a prophylactic measure. An analysis of records from >150,000 women with stage I-III disease from the SEER database demonstrated that contralateral prophylactic mastectomy rates have increased from 4.2% in 1998 among women already receiving therapeutic mastectomy to 11.0% in 2003.

Most recently, a large, population-based study of women with early-stage breast cancer treated with lumpectomy and radiation found that women who chose the breast-conserving option had both better disease-specific and overall survival compared with their mastectomy counterparts.

Our goal should not be to raise the thermometer up to the highest possible level of breast conservation. The patients I see are highly educated, and we should work with our patients to make sure that with all of the data and the storm of facts that swirl around them in their lives, we wind up in a place where they are happy with their decision. I’ve heard some surgeons say that we shouldn’t mention mastectomy for their stage I breast cancer patients. I don’t really understand that. If 62% of surgeons treating breast cancer patients in an American College of Surgeons survey say, “I would choose mastectomy,” how do we not mention that to our patients? Our goal should be to match patient concerns, values, and priorities with their treatment choice. The best we can hope for is to establish a good enough relationship with our patients that we wind up getting it right as often as possible.

Mastectomy in the right patient is the right operation. The problem is, there is huge variation within and between countries in the number of women treated by mastectomy, and there are also huge variations in the mastectomy rate even in the same unit, depending on the surgeon you see. This has to be wrong. Recently published research has shown that survival may be better with breast-conserving surgery and radiation than with mastectomy alone.10 We also have a big problem with breast screening—we’re overdiagnosing cancer that previously wouldn’t even have appeared in a woman’s life, and therefore we have to be careful that we don’t overtreat. The primary reason for patients choosing mastectomy is fear of recurrence, but recurrence rates are falling, and the majority of patients may not be well enough informed to make an evidence-based choice. The outcomes from mastectomy and breast reconstruction are not as good as we think or as good as we tell our patients.

			Treatment of Early-Stage Breast Cancer. NIH Consens Statement Online 1990 Jun 18-21;8(6):1-19.

			Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. 

			Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. 

			Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial. 

			Lazovich D, Solomon CC, Thomas DB, et al. Breast conservation therapy in the United States following the 1990 National Institutes of Health Consensus Development Conference on the treatment of patients with early stage invasive breast carcinoma. 

			Freedman RA, He Y, Winer EP, et al. Trends in racial and age disparities in definitive local therapy of early-stage breast cancer. 

			Mahmood U, Hanlon AL, Koshy M, et al. Increasing national mastectomy rates for the treatment of early stage breast cancer [published online ahead of print November 2012]. 

			Garcia-Etienne CA, Tomatis M, Heil J, et al. Mastectomy trends for early-stage breast cancer: a report from the EUSOMA multi-institutional European database. 

			Tuttle TM, Habermann EB, Grund EH, et al. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. 

			Hwang ES, Lichtenstein DY, Gomez, Fowble B, Clarke CA. Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status. 

A review of several studies examining the long-term benefits of breast-conservation therapy compared with mastectomy for women with stage breast cancer.

Jennifer Klem, PhD

Articles

G-CSF Underused in Older Patients Receiving Immunochemotherapy for DLBCL

Identifying and Managing Endocrinopathies With Immune Checkpoint Inhibitors

Framing the Mastectomy Debate-The Trends