Estrogen Receptor Positive, HER 2 Negative Metastatic Breast Cancer

  • The use of an aromatase inhibitor (letrozole) with an inhibitor of the cyclin dependent kinases 4 and 6 (ribociclib):
    • Was compared with an aromatase inhibitor alone in postmenopausal women with hormone receptor positive HER2-negative metastatic breast cancer:
      • In the MONALEESA-2 study
  • MONALEESA-2 Trial:
    • Results showed an improvement with the addition of ribociclib to letrozole alone in:
      • Progression-free survival (PFS):
        • From 42.2% to 63%
      • Overall response rate:
        • From 37.1% to 52.7%
    • This regimen was also investigated in premenopausal women with advanced, hormone receptor-positive breast cancer, and improved PFS compared with placebo plus endocrine therapy
  • References
    • Hortobagi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med.2016;375(18)1738-1748.
    • Tripathy D, Im SA2, Colleoni M3, Franke F4, Bardia A5, Harbeck Nm et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915.
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Calcium Hemostasis Basics

  • Calcium:
    • Is the most abundant cation in the human body
  • As much as 99% of calcium:
    • Is stored in the musculoskeletal system
  • The remainder is present in serum and exists in three forms:
    • 45% is bound to albumin and is biologically inert
    • 50% is ionized and metabolically active
    • A small percentage is complexed with citrate and is also biologically inactive
  • Hypoalbuminemia means:
    • That more of the total serum calcium will be free and metabolically active
  • Although total serum calcium may be low:
    • The patient may not be metabolically hypocalcemic
  • Ionized calcium levels:
    • Are inversely affected by the pH of blood:
      • A one-unit rise in pH:
        • Will decrease the ionized calcium level by 0.36 mmol/L
  • Hypoventilation:
    • Would cause a drop in pH and thus a subsequent rise in the ionized calcium level

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Mandibulotomy

  • A mandibulotomy can be performed in one of three locations:
    • Lateral:
      • Through the body or angle of the mandible
    • Midline
    • Paramedian
  • A lateral mandibulotomy has several disadvantages:
    • First, the muscular pull on the two segments of the mandible is unequal:
      • Putting the mandibulotomy site under significant stress and causing a delay in healing:
        • For this reason, intermaxillary fixation may be required
    • Second, the ability to gain access to the suture line to maintain cleanliness following surgery in the oral cavity is hampered as a result of intermaxillary fixation leading to poor oral hygiene and the potential risk for sepsis of the suture line
    • Third, a lateral mandibulotomy poses several anatomic disadvantages including:
      • Denervation of the teeth distal to the mandibulotomy site and the skin of the chin:
        • As a result of transection of the inferior alveolar nerve
      • A lateral mandibulotomy also causes devascularization of the distal teeth and the distal segment of the mandible:
        • From its endosteal blood supply
      • The exposure provided by a lateral mandibulotomy:
        • Is limited
      • If the patient needs postoperative radiation therapy:
        • Delayed healing can lead to complications at the site of the mandibulotomy
    • For these reasons, a lateral mandibulotomy:
      • Is not recommended
  • By placing the mandibulotomy in the anterior midline:
    • All the disadvantages of a lateral mandibulotolotomy:
      • Are avoided
    • However, splitting the mandible in the midline:
      • Requires extraction of one central incisor tooth:
        • To avoid exposure of the roots of both central incisor teeth:
          • Which are at risk of extrusion
        • Extraction of one central incisor tooth alters the aesthetic appearance of the lower dentition
      • In addition, a midline mandibulotomy requires:
        • Division of muscles arising from the genial tubercle, that is:
          • The geniohyoid and genioglossus:
            • Leading to a delayed recovery of the functions of mastication and swallowing
    • Therefore a median mandibulotomy:
      • Also is not preferred for these reasons
  • A paramedian mandibulotomy:
    • On the other hand, avoids all the disadvantages of a lateral mandibulotomy and the sequelae of a midline mandibulotomy
    • It offers significant advantages, such as:
      • Wide exposure
      • Preservation of the geniohyoid and genioglossus muscles:
        • Leading to preservation of the hyomandibular complex
      • The only muscle requiring division is the mylohyoid muscle:
        • Which leads to minimal swallowing difficulties
    • A paramedian mandibulotomy:
      • Does not cause denervation or devascularization of the skin of the chin or the teeth and mandible
    • Fixation at the mandibulotomy site is easy
    • The site of the mandibulotomy is able to withstand radiation therapy if the patient needs postoperative treatment
  • Thus at present a paramedian mandibulotomy:
    • Remains an optimal surgical approach for access to posteriorly located larger lesions of the oral cavity and tumors of the oropharynx and parapharyngeal space

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SURGICAL APPROACHES FOR ORAL CAVITY CANCERS

  • A variety of surgical approaches:
    • Are available for resection of primary tumors of the oral cavity
  • The choice of a particular approach will depend on factors such as:
    • The size and site (anterior versus posterior) of the primary tumor
    • As well as its depth of invasion
    • Proximity to the mandible or maxilla
  • Factors such as dentition, size of the oral aperture, trismus, and the size and mobility of the tongue:
    • Also influence selection of the surgical approach
  • The various surgical approaches such as:
    • Peroral, mandibulotomy, lower cheek flap approach, visor flap approach, and upper cheek flap approach are shown in Figure
  • The transoral approach has wider applications with technologic advances using:
    • Lasers (transoral laser microsurgery [TLM]) and robotics (transoral robotic surgery [TORS])
Various surgical approaches. A, Peroral. B, Mandibulotomy.
C, Lower cheek flap. D, Visor flap. E, Upper cheek flap.
  • When the peroral approach does not offer adequate exposure:
    • The visor flap or cheek flap approaches (upper or lower) become necessary
  • The visor flap approach:
    • Provides sufficient exposure for anteriorly located lesions:
      • But is not satisfactory for tumors located in the posterior oral cavity
    • The benefit of this approach is that it avoids a lower lip–splitting incision:
      • But produces permanent numbness of the chin:
        • Because the mental nerves need to be transected for adequate mobilization of the flap
      • It also may cause sagging of the lower lip and drooling:
        • Because of a loss of support and sensation:
          • Thus its utility is limited
  • The lower cheek flap approach:
    • Requires a midline lip–splitting incision that is continued laterally into the neck for exposure and neck dissection:
      • This approach provides excellent exposure for nearly all tumors of the oral cavity:
        • Except those of the upper gum and hard palate
  • Mandible resection (marginal or segmental) and reconstruction:
    • Require the lower cheek flap approach in most instances
  • The lower cheek flap approach:
    • Is required for marginal or segmental mandibulectomy of tumors adjacent to the body of the mandible
  • The upper cheek flap approach (the Weber-Ferguson incision and its modifications):
    • Is required for resection of larger tumors of the hard palate and upper alveolus:
      • Particularly if they are posteriorly located
  • Access to larger tumors of the tongue, particularly those closer to the base of the tongue where the mandible is not involved:
    • Requires wider exposure for resection:
      • A mandibulotomy or mandibular osteotomy is an excellent mandible sparing surgical approach designed to gain access to the oral cavity or oropharynx for resection of primary tumors otherwise not accessible through the open mouth or by the lower cheek flap approach (Figure)
A mandibulotomy is an excellent mandible-sparing surgical
approach to gain access to bulky tumors of the oral cavity or
oropharynx.

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NCCN Clinical Practice Guidelines Recommend FES PET Imaging for ER Positive Breast Cancer

  • The latest National Comprehensive Cancer Network (NCCN) clinical practice guidelines:
    • Have added fluoroestradiol F18 (FES) PET scan to its list of considerations for patients with recurrent or metastatic ER breast cancer
  • The NCCN guideline now recommends clinicians consider the use of FES PET for ER-positive disease during work-up of patients with recurrent or metastatic breast cancer
  • The guideline update follows the publication of the Society of Nuclear Medicine and Molecular Imaging’s appropriate use criteria statement on ER-targeted PET imaging in March of 2023:
    • Which noted that FES PET is appropriate when a clinician is considering endocrine therapy and assessing ER status at initial diagnosis of metastatic breast cancer, when the disease progresses after endocrine therapy, when lesions are challenging or dangerous to biopsy, and / or when other tests evaluating ER status are inconclusive
  • The addition to FES PET in the NCCN guidelines in addition to fluorodeoxyglucose gives clinicians an opportunity to assess ER function in all tumor sites in patients with ER-positive metastatic breast cancer
  • FES was approved by the FDA for use as an adjunct to biopsy in patients with recurrent or metastatic breast cancer in May 2020 and is currently the only imaging agent approved by the agency for that indication:
    • This is a helpful tool for diagnostic confirmation and may have the ability to aid in prognosis and prediction of clinical benefit from endocrine based therapies, including with CDK 4/6 inhibitors
    • We have many endocrine options now, and FES PET may identify patients who remain ER+ and thus potentially benefit from endocrine based therapy
  • References: 

Depth of Invasion in Oral Cavity Cancer

  • The staging of primary tumors of the oral cavity:
    • As published by the AJCC and UICC is widely accepted
  • In its most recent revision (eighth edition of the AJCC Staging Manual):
    • Depth of invasion (DOI):
      • Is added to the surface dimensions and local extent of the tumor:
        • As the required parameters for primary tumor staging in the oral cavity
Depth of invasion and surface dimensions are the
parameters required for T staging of oral cancer
  • Accurate assessment of DOI by clinical examination is not possible:
    • However, the staging system stratifies DOI by 5 mm increments, and thus clinical estimates of DOI can be categorized into:
      • Thin (less than 5 mm)
      • Thick (5 to 10 mm)
      • Very thick (greater than 10 mm)
        • By palpation to assign clinical T stage
Primary tumors of the oral cavity are categorized as thin,
thick, and very thick by palpation
  • The stage distribution of patients with squamous cell carcinoma of the oral cavity at the Memorial Sloan Kettering Cancer Center in New York is shown in the graph:
Stage distribution for squamous cell carcinoma of the oral cavity
(MSKCC data 1985 to 2015)
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The Current Indications for a Segmental Mandibulectomy

  • The current indications for a segmental mandibulectomy include:
    • Gross invasion by an oral cavity cancer
    • Invasion of the inferior alveolar nerve or canal by the tumor
    • Massive soft-tissue disease adjacent to the mandible
    • A primary malignant tumor of the mandible
    • A tumor that has metastasized to the mandible
Types of Mandibulectomy
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CREATE-X Trial in Breast Cancer

  • The CREATE-X trial:
    • Randomly assigned 910 patients:
      • With HER2 negative breast cancer and residual disease after undergoing neoadjuvant chemotherapy:
        • To standard postsurgical treatment and capecitabine or placebo
  • The primary end point:
    • Was disease-free survival (DFS)
  • Secondary end points included:
    • Overall survival (OS)
  • DFS was longer in the capecitabine group than in the control group (placebo):
    • 74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years
  • Among patients with triple-negative disease:
    • DFS was 69.8% in the capecitabine group versus 56.1% in the control group
  • OS rate was 78.8% versus 70.3%
  • There is no role for tamoxifen or anastrozole in triple negative breast cancer
  • Residual disease after completion of neoadjuvant chemotherapy:
    • Is associated with worse outcomes

References

1. Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Eng J Med. 2017;376(22):2147-2159.

2. Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060.

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Patients with Breast Cancer That Converts from Lymph Node-Positive to -Negative Can Skip Adjuvant Regional Nodal Irradiation

  • The omission of adjuvant regional nodal irradiation did not appear to increase the risk for recurrence or death among patients with breast cancer whose disease converted from lymph node-positive to lymph node-negative after neoadjuvant chemotherapy, according to research presented at the 2023 San Antonio Breast Cancer Symposium
  • There is no standard of care in place for patients with breast cancer for whom neoadjuvant chemotherapy has eliminated lymph node involvement, the researchers explained
  • The researchers performed a phase 3 clinical trial of 1,641 patients with lymph-node positive, nonmetastatic breast cancer who were found to have no lymph node involvement after neoadjuvant chemotherapy and surgery
  • They randomly assigned patients to two different regimens:
    • One group was assigned to skip regional nodal irradiation after undergoing mastectomy or whole breast irradiation and breast-conserving surgery
    • The other group was assigned to continue with chest wall irradiation and regional nodal irradiation following mastectomy or whole-breast irradiation plus regional nodal irradiation and breast-conserving surgery
  • Median follow-up was 59.5 months, and patients were a median of 52 years old
  • Seventy-eight percent had experienced a complete breast pathological response
  • In the “no regional nodal irradiation group,” 91.8% of patients were invasive breast cancer-recurrence free at 5 years compared with 92.7% of those who did undergo regional nodal irradiation
  • In both groups, 93.4% of patients were reported to be distant-recurrence free at 5 years
  • Overall survival was 94% in patients who were assigned to skip regional nodal irradiation and 93.6% in those who did not skip the therapy, according to the researchers
  • The researchers are planning a longer-term follow-up to further examine their findings, and a 10-year analysis time point was reached this past year
  • There findings suggest that downstaging cancer-positive regional lymph nodes with neoadjuvant chemotherapy can allow some patients to skip adjuvant regional nodal irradiation without adversely affecting oncologic outcomes
    • Follow-up of patients for long-term outcomes continues
  • Reference: 
    • Mamounas, E. Loco-regional irradiation in patients with biopsy-proven axillary node involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: Primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304. Abstract GS02-07. SABCS 2023

Pathway by Which Oral Cancers Invade the Mandible

  • To determine the need and extent of mandible resection:
    • It is essential to understand the pathway by which oral cancers invade the mandible
  • Primary carcinomas of the lip, buccal mucosa, tongue, and floor of the mouth:
    • Extend along the surface mucosa and the submucosal soft tissues:
      • To approach the attached labial, buccal, or lingual gingiva
    • From this point:
      • The tumor does not extend directly through intact periosteum and cortical bone toward the cancellous part of the mandible:
        • Because the periosteum acts as a significant protective barrier
    • Instead:
      • The tumor advances from the attached gingiva toward the alveolus:
        • In patients with teeth, the tumor extends through the dental socket into the cancellous part of the bone and invades the mandible in that fashion (Figure)
Tumor invasion of the dentate mandible occurs through
the dental socket to the cancellous bone and then to the alveolar canal
  • In edentulous patients:
    • The tumor extends up to the alveolar process and then infiltrates the dental pores in the alveolar ridge and extends to the cancellous part of the mandible (Figure)

 

Tumor invasion of the edentulous mandible occurs
through the dental pores on the alveolar process to the cancellous bone
and then to the alveolar canal.
  • Thus even in patients with early invasion of the mandible:
    • A marginal mandibulectomy is feasible because the cortical part of the mandible inferior to the roots of the teeth:
      • Remains uninvolved and can be safely spared
  • In edentulous patients, however, the feasibility of marginal mandibulectomy depends on the vertical height of the body of the mandible:
    • With aging, the alveolar process recedes and the mandibular canal comes closer to the surface of the alveolar process:
      • As shown in the Figure, the resorption of the alveolar process eventually leads to a “pipestem” mandible in elderly patients
Vertical height and location of the alveolar canal in
dentate and edentulous mandibles.
  • The ability to perform a satisfactory marginal mandibulectomy in such patients is almost impossible:
    • Because the probability of iatrogenic fracture or postsurgical spontaneous fracture of the remaining portion of the mandible is very high:
      • Similarly, in patients who have received previous radiotherapy, a marginal mandibulectomy should be performed with extreme caution:
        • The probability of pathological fracture at the site of the marginal mandibulectomy in such patients is very high
  • When the tumor extends to involve the cancellous part of the mandible:
    • A segmental mandibulectomy must be performed
    • A segmental mandibulectomy also may be required in patients with massive primary tumors with significant soft tissue disease in the proximity of the mandible

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

image-49

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

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• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

image-51

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