Christopher J. Anker

Melanoma, version 4.2014: Featured updates to the NCCN guidelines

The NCCN Guidelines for Melanoma provide multidisciplinary recommendations on the clinical management of patients with melanoma. This NCCN Guidelines Insights report highlights notable recent updates. Foremost of these is the exciting addition of the novel agents ipilimumab and vemurafenib for treatment of advanced melanoma. The NCCN panel also included imatinib as a treatment for KIT-mutated tumors and pegylated interferon alfa-2b as an option for adjuvant therapy. Also important are revisions to the initial stratification of early-stage lesions based on the risk of sentinel lymph node metastases, and revised recommendations on the use of sentinel lymph node biopsy for low-risk groups. Finally, the NCCN panel reached clinical consensus on clarifying the role of imaging in the workup of patients with melanoma.

Severe Liver and Skin Toxicity After Radiation and Vemurafenib in Metastatic Melanoma

Case Report A 15-year-old girl underwent wide local excision and sentinel lymphadenectomy of a thin, nonulcerated melanoma. One of 16 lymph nodes contained a focus of microscopic metastasis. Staging imaging showed no other disease. After the first of 12 planned months of adjuvant interferon alfa, the medication was discontinued early because of significant fatigue. New lung nodules were detected on surveillance computed tomography (CT) imaging 3 years after diagnosis, and a biopsy confirmed melanoma. Magnetic resonance imaging (MRI) of the brain also showed a new metastasis to the right parietal bone. The patient was started on high-dose interleukin-2. Follow-up MRI showed local progression of the skull lesion, so stereotactic radiation (RT) involving 25 Gy over five treatments was given after her second interleukin-2 cycle. Adverse effects of RT included alopecia and faint erythema in the radiated area. The patient developed back pain, and surveillance CT scans 2 weeks later showed new bone metastases in the axial skeleton, liver and spleen metastases, and progression in her lungs. BRAF mutation testing of a subcutaneous metastasis that was excised from the back showed a V600E mutation. The patient was enrolled onto a phase II study investigating vemurafenib in metastatic melanoma that was approved by the institutional review board of the University of California, Los Angeles. Her initial vemurafenib dose was 960 mg twice per day. Within 14 days, her performance status improved, with a substantial decrease in her spinal pain. No photosensitivity was observed. After 1 month, CT scans showed progression of bone metastases, but the disease in her liver, lungs, and spleen was either stable or decreased. After withholding vemurafenib for 4 days, 20 Gy of RT was administered over five fractions to the painful bone metastases. A posterior-anterior (PA) beam was used for T1 to T7 and T10 to L1, and her bilateral acetabula were treated with an AP/PA arrangement. Vemurafenib was restarted 2 days after the completion of RT. Two weeks after RT, the patient developed a tender, raised rash with well-delineated borders that matched her RT portals (Fig 1, portals are indicated in yellow; Fig 2, portals are indicated in cyan). Dry desquamation and then resolution of the skin changes occurred within 4 weeks. Imaging performed 3 weeks after RT showed overall stability of non-CNS disease, but 12 new brain metastases were detected. Although whole-brain therapy would be standard treatment in this scenario, because of significant concerns about skin toxicity, stereotactic radiosurgery (SRS) to each brain metastasis was recommended. Two weeks later the patient developed lower extremity weakness, and a lumbar spine MRI showed cauda equina compression at L4. She received 8 Gy of RT to L2 to L5 using a PA field, but vemurafenib was only withheld for 2 days because of the emergent nature of the treatment. Three days later, 20-Gy SRS was performed on each of the brain metastases. Vemurafenib was restarted 4 days after SRS, beginning at 480 mg for 3 days before moving to a full dose. Approximately 1 week after RT, she developed only mild erythema that matched the L2 to L5 portal. CT scans performed 10 weeks after the completion of her second course of RT showed interval pulmonary progression, with mixed responses elsewhere. Of concern was the development of innumerable, tightly packed, hypodense lesions in the liver that matched her previous RT portal (Fig 3A, pretreatment scan, black arrows indicate examples of liver metastases outside the RT portal; Fig 3B, posttreatment scan with RT isodose overlay [100 cGy 1 Gy]). Days later the patient developed severe chest discomfort and was admitted for pain control. The following 3 days she developed worsening abdominal pain and an acute drop in hematocrit. Interval accumulation of a large subcapsular hepatic hematoma and hemoperitoneum consistent with hepatic hemorrhage were detected on CT imaging (Fig 3C, white arrows). The patient died 2 days later. An autopsy showed an enlarged liver with multicystic change that was mostly limited to the central liver. Microscopically, these cysts were hemorrhagic and lined with melanoma cells (Fig 4A, 20 magnification of subcapsular cyst lined by melanoma. Organizing clot was seen emerging through ruptured cysts, explaining the sudden drop in hematocrit. Fig 4B, 40 magnification of multiple cysts lined by melanoma [arrow]; Fig 4C, 400 magnification). The intervening liver parenchyma showed severe zone III necrosis and scattered venous thrombi that were consistent with radiation-induced liver toxicity. However, outside of the radiation field, the liver also showed zone III necrosis, although it was less severe and without venous thrombi. This was suggestive of an additional source of liver damage subsequent to the initial insult, such as global ischemia. The late-occurring ischemic injury was likely the combined result of blood loss from a ruptured hematoma found at autopsy and multiorgan failure near the time of death.

Cross-sectional study of bone mineral density in adult survivors of solid pediatric cancers.

To investigate the hypothesis that survivors of pediatric solid cancer have low bone mineral density, a cross-sectional study was done of subjects who had received treatment for pediatric solid tumors before 16 years of age and were less than 40 years old at follow-up. Excluded were subjects treated for acute lymphoblastic leukemia or those who had received cranial irradiation, total body radiation, or nonautologous bone marrow transplant. The study group consisted of 38 subjects, with the most common diagnoses being lymphoma (n = 17), sarcoma (n = 8), Wilms tumor (n = 5), and neuroblastoma (n = 4). Median age was 22 years (range 12-32). Time from diagnosis of underlying cancer averaged 12.6 years (range 5.5-20.3). Using criteria of osteopenia (Z-score ≤−1.0 and >−2.0) and osteoporosis (Z-score ≤ −2.0) for any one or more areas including total body, lumbar spine, total hip, or femoral neck density, 13 of the 38 subjects (34%) had osteopenia or osteoporosis. A further six subjects (16%) had isolated upper extremity osteopenia or osteoporosis. Multivariate analysis showed a direct relationship between the number of chemotherapy drugs administered and the presence of osteopenia or osteoporosis in the lower extremities (P = 0.03). Young survivors of childhood solid tumors are at increased risk of developing premature osteopenia or osteoporosis, and screening evaluations and follow-up are warranted.

Ultraporous beta-tricalcium phosphate is well incorporated in small cavitary defects.

Numerous bone graft substitutes are available as alternatives to autologous and allograft bone grafts. The use of ultraporous β-tricalcium phosphate for cavitary bone defects in our institution was based on the hypothesis that it would have gradual but complete incorporation over several months, similar to the smooth transition seen in animal models. This retrospective, uncontrolled study reviews 24 patients who had bone grafting of a cavitary defect with ultraporous β−tricalcium phosphate mixed with local blood. Radiographically, resorption and trabeculation increased steadily with time, with trabeculation lagging slightly behind resorption. Resorption and trabeculation were more advanced at times beyond 6 weeks in small defects (< 43 cm3) compared with large defects (≥ 43 cm3). The presence of peripheral radiolucency seen early around nearly all grafts disappeared in small lesions by 1 year, but still was visible in larger lesions at the latest followup. Bone renewal seems to correspond temporally with gradual replacement of graft material, but incorporation is not complete even at 1 year in large defects. Clinically, there is a low rate of complications associated with the use of ultraporous β-tricalcium phosphate, and patients progressed to unrestricted activities of daily living and recreational activities within 3 months. Level of Evidence: Therapeutic study, Level IV (case series—no, or historical control group). See the Guidelines for Authors for a complete description of levels of evidence.

Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment

OBJECT BRAF inhibitors improve progression-free and overall survival in patients with metastatic melanoma. Brain metastases are common, and stereotactic radiosurgery (SRS) has been used, resulting in excellent local control. Because BRAF inhibitors are associated with intracranial responses, the authors hypothesized that BRAF inhibitors would improve local control in patients with melanoma who are receiving SRS for brain metastases. METHODS The authors retrospectively identified patients with metastatic melanoma who had been tested for BRAF mutation and treated with SRS for brain metastases. Patients with previous resection, multiple brain metastases, or multiple courses of SRS were eligible. SRS was delivered in a single fraction to a median dose of 2000 cGy. Patients with a BRAF mutation were treated with a BRAF inhibitor on the basis of physician preference. RESULTS The authors identified 52 patients who were treated in 82 treatment sessions for 185 brain metastases and 13 tumor beds. At a median follow-up of 10.5 months, the 1-year local control rate was 69.2%. At 1 year, the local control rate for brain metastases in patients with BRAF mutation with BRAF treatment was 85.0%, and the local control rate for brain metastases in those without BRAF treatment was 51.5% (p = 0.0077). The rates of distant brain failure, freedom from whole-brain radiation, and overall survival were not different on the basis of BRAF mutation status or inhibitor therapy. The number of new intratumoral hemorrhages after SRS was increased significantly in patients with BRAF treatment. CONCLUSIONS Treatment with BRAF inhibitors was associated with improved local control after SRS in patients with melanoma and brain metastases. An increased number of intratumoral hemorrhages was associated with BRAF inhibitor therapy.

Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial

Importance The role of epidermal growth factor receptor (EGFR) inhibition in chemoradiation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain. Objective To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma. Design, Setting, and Participants A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013. Interventions Patients were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m2 on day 1 then 250 mg/m2 weekly). Main Outcomes and Measures Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided &agr; = .025. Results Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47% (95% CI, 38%-57%) and 49% (95% CI, 40%-59%) vs 49% (95% CI, 41%-58%) and 49% (95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45% (95% CI, 37%-53%) and 34% (95% CI, 26%-41%) vs 44% (95% CI, 36%-51%) and 28% (95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47). Conclusions and Relevance The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer. Trial Registration clinicaltrials.gov Identifier: NCT00655876

Does the entire uterus need to be treated in cancer of the cervix? Role of adaptive brachytherapy.

PURPOSE To evaluate local control and toxicity by use of a method of adaptive cervical brachytherapy (ACB). METHODS AND MATERIALS From 1998 to 2008, we identified 65 cervical cancer patients with FIGO (International Federation of Gynecology and Obstetrics) Stage IB1-IVA disease who received definitive external beam radiation therapy and high-dose rate brachytherapy with tandem and ovoid applicators. As tumors regressed, 45 of 65 patients had the tandem source retracted from the uterine fundus at successive brachytherapy insertions, thus decreasing the number of (192)Ir dwell positions. Tests of trend and Fishers exact test were used to identify the effect of ACB on disease control and toxicity. Kaplan-Meier analyses were performed to evaluate disease control and late complications. RESULTS The median follow-up was 24.5 months. Of the patients, 92% received chemotherapy. The 3-year overall survival, 3-year disease-free survival, 3-year distant metastasis-free survival, and local control rates were 67%, 76%, 79%, and 97%, respectively. There was only 1 isolated local failure, and there were no local failures beyond 1 year. Distant failure was involved in 93% of recurrences. No significant trend was identified regarding the extent of retraction of the tandem source start position with either failure or toxicity. Acute and actuarial 3-year late Grade 3 toxicity or greater occurred in 24.6% and 17% of patients, respectively. CONCLUSIONS ACB determined by clinical response yielded excellent local control rates. These data indicate that ACB may be useful in decreasing late toxicities from high-dose rate brachytherapy. With the advent of three-dimensional image-guided brachytherapy, additional methods to adapt treatment technique to changes in tumor volume warrant investigation.

The Effect of Radiation on Complication Rates and Patient Satisfaction in Breast Reconstruction using Temporary Tissue Expanders and Permanent Implants

The optimal method of reconstruction following mastectomy for breast cancer patients receiving radiation therapy (RT) is controversial. This study evaluated patient satisfaction and complication rates among patients who received implant‐based breast reconstruction. The specific treatment algorithm analyzed included patients receiving mastectomy and immediate temporary tissue expander (TE), followed by placement of a permanent breast implant (PI). If indicated, RT was delivered to the fully expanded TE. Records of 218 consecutive patients with 222 invasive (85%) or in situ (15%) breast lesions from the Salt Lake City region treated between 1998 and 2009 were retrospectively reviewed, 28% of whom received RT. Median RT dose was 50.4 Gy, and 41% received a scar boost at a median dose of 10 Gy. Kaplan–Meier analyses were performed to evaluate the cumulative incidence of surgical complications, including permanent PI removal. Risk factors associated with surgical events were analyzed. To evaluate cosmetic results and patient satisfaction, an anonymous survey was administered. Mean follow‐up was 44 months (range 6–144). Actuarial 5‐year PI removal rates for non‐RT and RT patients were 4% and 22%, respectively. On multivariate analysis (MVA), the only factor associated with PI removal was RT (p = 0.009). Surveys were returned describing the outcomes of 149 breasts. For the non‐RT and RT groups, those who rated their breast appearance as good or better were 63% versus 62%, respectively. Under 1/3 of each group was dissatisfied with their reconstruction. RT did not significantly affect patient satisfaction scores, but on MVA RT was the only factor associated with increased PI removal. This reconstruction technique may be considered an acceptable option even if RT is needed, but the increased complication risk with RT must be recognized.

Patterns of failure and predictors of outcome in cutaneous malignant melanoma of the scalp

BACKGROUND Patients with melanoma of the scalp may have higher failure (recurrence) rates than melanoma of other body sites. OBJECTIVE We sought to characterize survival and patterns of failure for patients with scalp melanoma. METHODS Between 1998 and 2010, 250 nonmetastatic patients underwent wide local excision of a primary scalp melanoma. Kaplan-Meier analyses were performed to evaluate overall survival, scalp control, regional neck control, distant metastases-free survival, and disease-free survival. RESULTS Five-year overall survival was 86%, 57%, and 45% for stages I, II, and III, respectively, and 5-year scalp control rates were 92%, 75%, and 63%, respectively. Five-year distant metastases-free survival for these stages were 92%, 65%, and 45%, respectively. Of the 74 patients who recurred, the site of first recurrence included distant disease in 47%, although 31% recurred in the scalp alone. LIMITATIONS This is a retrospective review. CONCLUSION Distant metastases-free survival and overall survival for stage II and III patients with scalp melanoma are poor, and stage III patients experience relatively high rates of scalp failure suggesting that these patients may benefit from additional adjuvant systemic and local therapy. Further research is needed to characterize the environmental, microenvironmental, and genetic causes of the increased aggressiveness of scalp melanoma and to identify more effective treatment and surveillance methods.

Clinical outcomes associated with evolving treatment modalities and radiation techniques for base-of-tongue carcinoma: Thirty years of institutional experience

Curative treatment for base‐of‐tongue squamous cell carcinoma (BOT SCC) has evolved over time; however, comparative outcomes analysis for various treatment strategies is lacking. The authors reviewed the evolution of treatment modality and radiotherapy (RT) technique for 231 consecutive BOT SCC patients at our institution between 1981 and 2011. Treatment modalities included definitive chemoradiotherapy (chemoRT) (42%), definitive RT (33%), surgery followed by RT (20%), and surgery alone (5%). RT techniques included external beam plus interstitial brachytherapy (EBRT + IB) (37%), conventional EBRT (29%), intensity‐modulated radiation therapy ± simultaneous integrated boost (IMRT ± SIB) (34%). Clinical characteristics and outcomes were stratified by modality or RT technique. Treatment modality evolved from definitive RT (1980s–1990s) to definitive chemoRT (1990s–2000s). RT technique evolved from EBRT + IB (1980s–1990s) to conventional EBRT (1990s–2000s) to IMRT + SIB (2000s). With median alive follow‐up of 6 years (0.3–28 years), the 5‐year LC, LRC, and OS rates were 80%, 73%, and 51%. There was no difference in distribution of gender, age, stage among treatment modalities. Definitive chemoRT had improved LRC (HR 1.6) and OS (HR 1.7) compared to definitive RT. IMRT + SIB had improved LRC (HR 3.2), DFS (HR 3.4), and OS (HR 3.0) compared to conventional EBRT. Over the past 30 years, BOT SCC treatment has undergone major paradigm shifts that incorporate nonsurgical functional preservation, concurrent chemotherapy, and advanced RT techniques. Excellent locoregional control and survival outcomes are associated with accelerated IMRT with chemotherapy.