Temozolomide (Temodar)

Number: 0876

Policy

Aetna considers temozolomide (Temodar) injection medically necessary for the following indications:

  • Central nervous system cancers 
  • Cutaneous Melanoma  - metastatic or unresectable 
  • Ewing's sarcoma
  • Mycosis fungoides (MF)/Sezary syndrome (SS)
  • Neuroendocrine tumors - poorly differentiated (high-grade) / large or small cell 
  • Neuroendocrine tumors of the pancreas, gastrointestinal tract, lung and thymus 
  • Pheochromocytoma / paraganglioma
  • Primary cutaneous anaplastic large cell lymphoma (ALCL)
  • Small cell lung cancer (SCLC) 
  • Soft tissue sarcoma 
  • Uterine sarcoma
  • Uveal Melanoma  - distant metastatic

Aetna considers continued treatment with temozolomide (Temodar) medically necessary in members requesting reauthorization for a medically necessary indication when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers temozolomide injection experimental and investigational for all other indications including the following (not an all-inclusive list):

  • Chronic lymphocytic leukemia
  • Diffuse large B-cell lymphoma
  • Metastatic colorectal cancer
  • Neuroblastoma
  • Pituitary tumors (adenomas, carcinomas, Crooke's cell corticotropinoma, and prolactinoma)

For temozolomide (Temodar) tablets, see Pharmacy CPB on Antineoplastics.

Dosing Recommendations

Temozolomide for injection is available as Temodar 100-mg vials.

Refer to protocol by which member is being treated.  Numerous dosing schedules exist and depend on disease, response and concomitant therapy.  Guidelines for dosing also include consideration of absolute neutrophil count (ANC).  Dosage may be reduced, delayed or discontinued in member with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Newly Diagnosed GBM: 75 mg/m2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1-5 of a 28-day cycle of temozolomide for 6 cycles.

Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle.

The recommended dose for temozolomide as an intravenous infusion over 90 minutes is the same as the dose for the oral capsule formulation. Bioequivalence has been established only when temozolomide for injection was given over 90 minutes. 

Source: Temodar Prescribing Information. 

Background

Temodar (temozolomide) is an alkylating antineoplastic agent. Temodar (temozolomide) undergoes rapid chemical conversion at physiologic pH to the active compound, monomethyl triazeno imidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to methylation of DNA at the O6 and N7 positions of guanine. Both temozolomide and dacarbazine are prodrugs of MTIC. The formation of Omethylguanine inhibits DNA replication through errant repair of the methyladduct and causes cell death via stimulation of p53 and apoptosis. Temodar (temozolomide) is cell-cycle non‐specific; however, cell cycle arrest usually occurs between the G2‐ and M-phases. The combination of Temodar (temozolomide) and radiation therapy results in additive effects.

Temodar (temozolomide) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. The labeling states that temozolomide is indicated for the treatment of adult patients with refractory anaplastic astrocytoma (i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine).

Nausea and vomiting are known side effects of treatment and  should be medically treated, when they occur.  Current dosing recommendations by the manufacturer are not to withhold doses due to the adverse effects of vomiting.  Grade 3 or 4 vomiting occurred less than 1% in the clinical trials. 

Temozolomide is contraindicated in member with a history of hypersensitivity to dacarbazine.

Patient treated with Temodar (temozolomide) may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, patient must have an absolute neutrophil count (ANC) ≥1.5 × 109/L and a platelet count ≥100 × 109/L. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 × 109/L and platelet count exceeds 100 × 109/L. Geriatric patient and women have been shown in clinical trials to have a higher risk of developing myelosuppression.

For treatment of newly diagnosed glioblastoma multiforme: Prophylaxis against Pneumocystis carinii pneumonia is required for all patient receiving concomitant Temodar (temozolomide) and radiotherapy for the 42‐day regimen. There may be a higher occurrence of PCP when Temodar (temozolomide) is administered during a longer dosing regimen. However, all patients receiving Temodar (temozolomide), particularly patient receiving steroids, should be observed closely for the development of PCP regardless of the regimen.

Temodar (temozolomide) should be given with caution to patient with severe hepatic disease, renal impairment (creatinine clearance < 36 ml/min), or renal failure. The pharmacokinetics of Temodar (temozolomide) has not been studied adequately in these patient populations.

Vaccination during Temodar (temozolomide) therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patient should be avoided.

Extended Maintenance Temozolomide for Newly Diagnosed Glioblastoma

Gramatzki and colleagues (2017) examined an association with survival of modifying the current standard of care for patients with newly diagnosed glioblastoma of surgery followed by radiotherapy plus concurrent and 6 cycles of maintenance temozolomide chemotherapy (TMZ/RT → TMZ) by extending TMZ beyond 6 cycles.  The German Glioma Network cohort was screened for patients with newly diagnosed glioblastoma who received TMZ/RT → TMZ and completed greater than or equal to 6 cycles of maintenance chemotherapy without progression.  Associations of clinical patient characteristics, molecular markers, and residual tumor determined by magnetic resonance imaging (MRI) after 6 cycles of TMZ with progression-free survival (PFS) and overall survival (OS) were analyzed with the log-rank test.  Multi-variate analyses using the Cox proportional hazards model were performed to assess associations of prolonged TMZ use with outcome; 61 of 142 identified patients received at least 7 maintenance TMZ cycles (median of 11, range of 7 to 20).  Patients with extended maintenance TMZ treatment had better PFS (20.5 months, 95 % confidence interval [CI]: 17.7 to 23.3, versus 17.2 months, 95 % CI: 10.2 to 24.2, p = 0.035) but not OS (32.6 months, 95 % CI: 28.9 to 36.4, versus 33.2 months, 95 % CI: 25.3 to 41.0, p = 0.126).  However, there was no significant association of prolonged TMZ chemotherapy with PFS (hazard ratio [HR] = 0.8, 95 % CI: 0.4 to 1.6, p = 0.559) or OS (HR = 1.6, 95 % CI: 0.8 to 3.3, p = 0.218) adjusted for age, extent of resection, KPS, presence of residual tumor, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, or isocitrate dehydrogenase (IDH) mutation status.  The authors concluded that these findings may not support the practice of prolonging maintenance TMZ chemotherapy beyond 6 cycles.  This study provided Class III evidence that in patients with newly diagnosed glioblastoma, prolonged TMZ chemotherapy did not significantly increase PFS or OS.

Chronic Lymphocytic Leukemia

Rao and co-workers (2017) reported a case of incidentally diagnosed chronic lymphocytic leukemia (CLL) in a patient with glioblastoma, which responded completely following standard treatment of the glioblastoma with TMZ and cranial irradiation.  The patient remained without an evidence of CLL until his death from recurrent glioblastoma.  The authors stated that further study of TMZ for the treatment of CLL is indicated.

Diffuse Large B-Cell Lymphoma

Cencini and associates (2017) noted that central nervous system (CNS) relapse is an infrequent; but severe complication for patients with diffuse large B-cell lymphoma (DLBCL) associated with poor prognosis.  Intravenous prophylaxis with high-dose methotrexate has shown promising results but is rarely feasible in elderly and/or nephropathic patients.  A 83-year old woman with CNS relapse occurred 6 months after chemoimmunotherapy.  The patient was defined ineligible for radiotherapy (RT) and started oral TMZ 250-mg daily for 5 consecutive days without any improvement after 1st cycle.  These researchers administered lenalidomide 25-mg daily for 21 days every 28 days together with TMZ 250-mg daily for 5 days every 28 days.  The patient experienced a rapid improvement of general and cognitive conditions; gadolinium-enhanced brain MRI showed a wide reduction of neoplastic tissue.  Patients maintained good clinical conditions with mild treatment toxicity until the end of the 6th cycle, when brain MRI showed disease progression and the patient died 1 month later.  The authors suggested lenalidomide could be a feasible option for CNS relapse in elderly DLBCL patients and it could be associated in future studies with other cytotoxic agents such as TMZ.

Metastatic Colorectal Cancer

Pishvaian and colleagues (2018) noted that poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors such as veliparib are potent sensitizing agents and have been safely combined with DNA-damaging agents such as TMZ.  The sensitizing effects of PARP inhibitors are magnified when cells harbor DNA repair defects.  In a single-arm, open-label, phase-II clinical trial, these investigators examined the disease control rate (DCR) after 2 cycles of veliparib plus TMZ in patients with metastatic colorectal cancer (mCRC) refractory to all standard therapies.  A total of 50 patients received TMZ (150 mg/m2/day) on days 1 to 5 and veliparib (40 mg twice-daily) on days 1 to 7 of each 28-day cycle.  Another 5 patients with mismatch repair-deficient (dMMR) tumors were also enrolled; 20 additional patients were then treated with TMZ at 200 mg/m2/day.  Archived tumor specimens were used for immunohistochemistry (IHC) to assess mismatch repair, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression levels.  The combination was well-tolerated, although some patients needed dose reductions for myelosuppression.  The primary end-point was successfully met with a DCR of 24 % and 2 confirmed partial responses (PRs).  The median PFS was 1.8 months, and the median OS was 6.6 months; PTEN protein expression and MGMT protein expression were not predictors of DCR.  There was also a suggestion of worse outcomes for patients with dMMR tumors.  The authors concluded that in this heavily pre-treated mCRC population, a combination of veliparib and TMZ was well-tolerated with TMZ doses up to 200 mg/m2/day, and it was clinically active.  They stated that PARP inhibitor-based therapy merits further exploration in patients with mCRC.

Myxopapillary Ependymomas

Fujiwara and colleagues (2018) noted that myxopapillary ependymomas are intra-dural tumors that grow from the terminal filum of the spinal cord.  Although they are classified as WHO grade I, they sometimes cause cerebrospinal fluid (CSF) dissemination or local recurrence.  In this report, these investigators described a case in which TMZ showed remarkable efficacy on a recurrent spinal myxopapillary ependymoma.  A 26-year old woman underwent resection of an intra-dural myxopapillary ependymoma at L5 initially.  Although an en bloc total resection, including the capsule, could be achieved, she needed 2 additional tumor resection surgeries with post-operative radiotherapy at L4 and at L3 (2 and 6 years after the initial surgery, respectively).  Moreover, 4 years after the initial surgery, a disseminated metastatic tumor occurred at T11/12 and local radiotherapy was not effective.  After the 3rd surgery, an aggressive adjuvant therapy was necessary because there was a high risk of another recurrence.  Therefore, TMZ was administered for 1 year.  After 6 months of TMZ treatment, remarkably, the disseminated metastatic tumor at T11/12 had disappeared completely.  Presently, 6 years after finishing the TMZ treatment, the follow-up MRI has shown no recurrence in the brain and whole spine.  The authors concluded that TMZ is usually used in the treatment of glioblastoma and, recently, it has been reported to be effective for the lower grade spinal gliomas including spinal intramedullary ependymomas.  However, for myxopapillary ependymomas, there has been no report that TMZ is effective.  According to these findings, TMZ could be one of the possible candidates for adjuvant therapy in multiple recurrent myxopapillary ependymomas.  These preliminary findings need to be further investigated.

Neuroblastoma

Dubois and associates (2018) stated that in phase-I testing, alisertib tablets with irinotecan and TMZ showed significant anti-tumor activity in patients with neuroblastoma.  This study sought to confirm activity of this regimen; evaluate an alisertib oral solution (OS); and evaluate biomarkers of clinical outcomes.  These researchers conducted a 2-stage, phase-II clinical trial of alisertib tablets (60 mg/m2/dose x 7 days), irinotecan (50 mg/m2/dose IV x 5 days), and TMZ (100 mg/m2/dose orally x 5 days) in patients with relapsed or refractory neuroblastoma.  The primary end-point was best objective response.  A separate cohort was treated with alisertib at 45 mg/m2 using OS instead of tablets.  Exploratory analyses sought to identify predictors of toxicity, response, and PFS using pooled data from phase-I, phase-II, and OS cohorts.  A total of 20 and 12 eligible patients were treated in the phase-II and OS cohorts, respectively.  Hematologic toxicities were the most common adverse events (AEs).  In phase-II, 4 PRs were observed in 19 evaluable patients (21 %).  The estimated PFS at 1 year was 34 %.  In the OS cohort, 3 patients (25 %) had 1st cycle dose-limiting toxicity (DLT).  Alisertib OS at 45 mg/m2 had significantly higher median Cmax and exposure compared to tablets at 60 mg/m2.  Higher alisertib trough concentration was associated with 1st cycle DLT, while MYCN amplification was associated with inferior PFS.  The authors concluded that this combination showed anti-tumor activity, particularly in patients with MYCN non-amplified tumors; data on an alisertib oral solution expanded the population able to be treated with this agent.

Pituitary Tumors

Barkhoudarian and colleagues (2018) noted that invasive, medically-refractory, and multiply-recurrent pituitary adenomas pose a rare but nevertheless significant challenge to conventional management modalities; TMZ has been reported to be useful as an adjunctive treatment in some patients.  These investigators described the efficacy of TMZ when used early in the management of invasive prolactinoma.  In this case-report, a 56-year old man presented with an invasive, refractory macroprolactinoma; and had failed long-term dopamine agonists, stereotactic radiosurgery and multiple trans-sphenoidal surgical resections, with persistent hyperprolactinemia and tumor progression.  He was consequently started on TMZ, and during the 11 cycles of TMZ therapy, the patient's prolactin level decreased from 696 ng/ml to 15.2 ng/ml with a greater than 90 % decrease in tumor size.  Nearly 6 years after discontinuing chemotherapy, the patient remained in sustained remission (prolactin level 3.1 ng/ml) requiring only 1.5 mg of cabergoline weekly, without radiographic or clinical evidence of tumor recurrence.  The authors concluded that TMZ could be effective in the management of medically and surgically refractory, invasive atypical prolactinomas resulting in normalization of prolactin levels and control of tumor size.  These researchers encouraged the inclusion of TMZ in the management of refractory, recurrent, and invasive prolactinomas, as a 4rth-line treatment strategy, after dopamine agonist treatment, trans-sphenoidal resection, and radiation therapy; they particularly advocated the early use of TMZ in aggressive and otherwise refractory prolactinomas.  This was a single-case study; its findings need to be further investigated.

Syro and associates (2018) reviewed the mechanism of action of TMZ as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.  These investigators stated that overcoming and treating TMZ resistance has been a difficult clinical challenge.  Although medical management of TMZ resistance is limited at this time, great strides to understand its underlying mechanisms are being taken.  They stated that it is evident that arduous challenges persist and that it is crucial that research focus on the development of novel drugs that either enhance the effectiveness of TMZ or overcome its resistance.

Furthermore, an UpToDate review on “Management of hyperprolactinemia” (Synder, 2018) does not mention temozolomide as a therapeutic option.

Gilis-Januszewska and co-workers (2018) noted that aggressive pituitary tumors causing Cushing's disease are very rare, difficult to treat, and usually resistant to conventional therapy.  There is growing evidence for the use of TZM as 1st-line chemotherapy in tumors resistant to repeated neurosurgery, radiotherapy and adrenalectomy.  These researchers presented the response to TMZ in a rare case of an aggressive pituitary tumor in the course of Cushing's disease and reviewed the literature referring to similar cases.  In this report, these investigators presented the case of a 61-year old man who was diagnosed with Cushing's disease in the course of a pituitary invasive macro-adenoma in 2011.  The patient underwent 4 transphenoidal non-radical neurosurgeries (2012, 2013) with rapid tumor progression, repeated non-radical bilateral adrenalectomy (2012, 2013) and stereotactic radiotherapy, and gamma knife surgery (2013, 2015).  Histopathological examination revealed macro-adenoma with high cell polymorphism and the presence of Crooke's cells, Ki- less than 2 %.  Since 2015 the patient has been treated with 6 cycles of TMZ (320 mg per day for 5 consecutive days, 28-day cycle) with clinical and biochemical improvement and stabilized tumor size and no side effects; TMZ was continued for up to 9 cycles with a stable serum level of cortisol and ACTH being observed.  However, clinical symptoms like headaches, visual field impairment, and finally hearing loss started to progress from the 8th cycle.  After the 9th cycle of TMZ, there was a sudden increase in the size of the tumor, impairment of the cortisol and ACTH level, marked deterioration of the clinical status with the recurrence of severe headaches, narrowing of the visual field and hearing loss.  At the beginning of 2016, a sudden clinical status and sight deterioration, strong headaches, drop of the right eyelid with widening of the pupil were observed.  The patient died in February 2016.  The authors concluded that the findings of this case suggested that the response to the TMZ treatment monotherapy in aggressive pituitary tumor causing Cushing's disease could be partial and restricted to 7 to 8 cycles followed by rapid progression of the tumor mass; thus further research should be performed regarding new methods to extend the responsiveness and duration of TMZ treatment and to examine predictors of responsiveness.

Almalki and colleagues (2017) stated that pituitary tumors represent 10 to 15 % of all intra-cranial tumors; of these, prolactinomas account for 40 to 50 % of cases.  Prolactinomas usually respond well to dopamine agonists (DA) as 1st-line therapy.  However, treatment resistance remains a concern.  Temozolomide is an oral alkylating agent that has shown promise in treating aggressive pituitary adenomas and carcinomas that are resistant to other therapies.  To-date, no control trials have been undertaken and only single-case reports of pituitary tumors treated with TMZ have been published.  These investigators performed a systematic literature search for studies reporting the use of TMZ for the treatment of prolactinomas that were resistant to standard therapy.  A total of 42 reported cases were identified and included in this analysis: 23 cases of prolactin-secreting adenomas and 19 of prolactin-secreting carcinomas.  Prior to TMZ administration, patients had exhibited tumor progression and had previously undergone various treatments including surgery, radiotherapy, and drug therapy.  Tumor shrinkage was reported in 76 % of patients.  Reduced prolactin levels were observed in 75 % of patients, while normalization of prolactin was reported in 8 %; TMZ failure occurred in 20.6 % of cases.  Most patients exhibited no serious adverse effects.  The authors concluded that TMZ has potential for the treatment of highly aggressive and resistant prolactin-secreting adenomas and carcinomas, as demonstrated by tumor shrinkage or complete response (CR) and normalization of hormone hyper-secretion, and exhibited good tolerability and few side effects.

Aydogan and associates (2018) noted that treatment of aggressive pituitary tumors may be challenging; TMZ is a promising agent when conventional treatment methods fail.  These researchers presented the findings of 3 patients with aggressive pituitary tumors with atypical morphology, who were resistant to conventional treatments and treated with TMZ; 1st case had a somatotroph adenoma, 2nd case had a corticotroph adenoma, and the 3rd a macro-prolactinoma.  These investigators also reviewed the literature reporting TMZ efficacy in corticotroph, mammotroph and somatotroph tumors of the pituitary; TMZ, 150 to 200 mg/m2 for 5 days in a 28-day schedule was given to all patients.  Among the 3 patients studied in this report, even though only the case of macro-prolactinoma had a favorable response to TMZ treatment, both radiological and hormonal recurrences occurred 30 months after cessation of TMZ treatment.  Then TMZ treatment was applied again.  Cases of corticotroph and somatotroph had progressed under TMZ treatment and patients were lost due to mass effect of the tumor.  Review of the literature demonstrated 67.3 %, 60 % and 26.7 % overall response rates (ORRs) to the TMZ treatment in prolactinoma, corticotropinoma and somatostatinoma cases, respectively.  The authors concluded that there is still a need to define response criteria uniformly to TMZ treatment in aggressive pituitary tumors and the duration of response should be reported for reliable evaluation of results.

National Comprehensive Cancer Network (NCCN) Recommendations

The NCCN Drugs and Biologics Compendium (NCCN, 2020) recommends Temodar for the following:

  • Ewing Sarcoma and Mesenchymal Chondrosarcoma - Used in combination with irinotecan with or without vincristine [2A for Ewing sarcoma, 2B for mesenchymal chondrosarcoma]
     
    • with or without radiation therapy for relapse
    • for progressive disease following primary treatment
    • as second-line therapy for metastatic disease
       
  • Adult Intracranial and Spinal Ependymoma (Excluding Subependymoma) - Consider as single-agent treatment or in combination with lapatinib for progression or recurrent disease, if received prior RT and any of the following [2B for combination with lapatinib; 2A for others]

    • gross total or subtotal resection
    • localized recurrence
    • evidence of metastasis (brain, spine, or CSF) 

  • Adult Low-Grade (WHO Grade II) Infiltrative Supratentorial Astrocytoma/Oligodendroglioma
     
    • Adjuvant therapy as a single agent [2A for concurrent followed by adjuvant treatment; 2B for adjuvant treatment alone]
       
      • following radiation therapy (RT) following attempted gross total resection with high-risk features, subtotal resection, or biopsy
      • with concurrent radiation followed by temozolomide alone after attempted gross total resection with high-risk features, subtotal resection, or biopsy
      • following attempted gross total resection with low-risk features [2B]

    • Treatment for recurrent or progressive low-grade disease [2B for chemotherapy alone if no prior fractionated external beam RT; 2A for all others]

      • as a single agent
      • as a single agent following radiation therapy (RT)
      • with concurrent radiation followed by temozolomide alone

  • Adult Medulloblastoma - Treatment for recurrence as a single agent in patients who have received prior chemotherapy [2A]
  • Anaplastic Gliomas
     
    • Adjuvant treatment as a single agent
       
      • with concurrent fractionated external beam radiation therapy (RT) followed by temozolomide alone for anaplastic oligodendroglioma (1p19q codeleted), anaplastic astrocytoma, and anaplastic oligoastrocytoma NOS [2A]
      • following fractionated external beam RT for anaplastic oligodendroglioma (1p19q codeleted), anaplastic astrocytoma or anaplastic oligoastrocytoma, NOS [2A]
      • as chemotherapy alone for anaplastic gliomas and patients with poor performance status (Karnofsky Performance Status [KPS] <60) if tumor is MGMT promoter methylated [2B]
         
    • Treatment of recurrent disease as a single agent or in combination with bevacizumab [2A]
       
  • Glioblastoma
     
    • Adjuvant treatment
       
      • with concurrent standard brain radiation therapy (RT) followed by temozolomide alone plus alternating electric field therapy for patients with good performance status (PS) and Karnofsky Performance Status (KPS) ≥60 [1]
      • with concurrent standard brain RT followed by temozolomide alone for patients with good PS (KPS ≥ 60) [1 for < 70 years; 2A for others]
      • concurrent with or after hypofractionated brain RT for patients ≤70 years with poor PS (KPS <60) [2A]
      • concurrent with or after hypofractionated brain RT followed by temozolomide alone for patients > 70 years with good PS (KPS ≥ 60) [2A]
      • as chemotherapy alone for patients > 70 years with good PS (KPS ≥ 60) and methylated MGMT promotor status [1]
      • as chemotherapy alone for patients with poor PS (KPS <60) and methylated MGMT promoter status [2A]
         
    • Treatment of recurrent disease as a single agent or in combination with bevacizumab [2A]
       
  • Central Nervous System Cancers - Limited Brain Metastases - Single-agent treatment for recurrent brain metastases in patients with stable systemic disease or reasonable systemic treatment options [2A]
  • Central Nervous System Cancers - Extensive Brain Metastases - Single-agent treatment for recurrent brain metastases in patients with stable systemic disease or reasonable systemic treatment options [2A]
  • Primary CNS Lymphoma
     
    • Induction therapy [2A]
       
      • in combination with high-dose methotrexate and rituximab
      • in combination with high-dose methotrexate and rituximab followed by post-RT temozolomide
         
    • Consider for consolidation therapy in patients with complete response or complete response unconfirmed (CRu) to induction therapy [2A]
       
      • in combination with high-dose methotrexate and rituximab
      • in combination with high-dose methotrexate and rituximab followed by post-RT temozolomide
         
    • Treatment as a single agent or in combination with rituximab for relapsed or refractory disease [2A]
       
      • may be considered in patients who received prior whole brain radiation therapy
      • in patients who received a prior high-dose methotrexate-based regimen without prior radiation therapy (RT) 
      • in combination with whole brain RT or involved field RT in patients who received a prior high-dose methotrexate-based regimen without prior RT after no response or short response duration (<12 months) to prior regimen
      • in patients who received prior high-dose chemotherapy with stem cell rescue 
         
  • Cutaneous Melanoma - Single agent therapy for metastatic or unresectable disease as second-line or subsequent therapy for disease progression or after maximum clinical benefit from BRAF targeted therapy [2A]
  • Neuroendocrine Tumors of the GI Tract, Lung, and Thymus (Carcinoid Tumors)
     
    • Management of clinically significant tumor burden or progressive locoregional advanced disease of the gastrointestinal tract and/or distant metastases in patients for whom there are no other treatment option [3]
    • Consider for management of locoregional bronchopulmonary disease [2A for use of temozolomide, 2B for adjuvant therapy] 
       
      • as adjuvant therapy with or without radiation following resection of stage IIIA intermediate grade (atypical) histology
         
    • Management of locoregional advanced bronchopulmonary/thymic disease as a single agent or in conjunction with capecitabine [2A]  *May be considered for intermediate-grade/atypical tumors with Ki-67 proliferative index and mitotic index in the higher end of the defined spectrum
       
      • as primary therapy
      • consider as subsequent therapy if progression on first-line therapy
         
    • Management of distant metastatic bronchopulmonary/thymic disease* as a single agent or in combination with capecitabine in patients with clinically significant tumor burden and low grade (typical) histology, evidence of progression, or intermediate grade (atypical) histology [2A]  *May be considered for intermediate-grade/atypical tumors with Ki-67 proliferative index and mitotic index in the higher end of the defined spectrum

      • as primary therapy
      • consider as subsequent therapy if progression on first-line therapy

    • Consider for poorly controlled carcinoid syndrome if disease in the gastrointestinal tract in combination with [3]
        
      • either octreotide LAR or lanreotide for persistent symptoms (i.e., flushing, diarrhea)
      • telotristat for persistent diarrhea

    • Consider for poorly controlled carcinoid syndrome if disease in the lung/thymus with or without capecitabine and in combination with [2A]

      • either octreotide LAR or lanreotide for persistent symptoms (i.e., flushing, diarrhea)
      • telotristat for persistent diarrhea

  • Neuroendocrine Tumors of the Pancreas - For the management of bulky, symptomatic, and/or progressive locoregional advanced disease and/or distant metastatic disease [2A]
     
    • as a single agent
    • in combination with capecitabine
       
  • Neuroendocrine and Adrenal Tumors - Poorly Differentiated (High Grade)/Large or Small Cell - Treatment with or without capecitabine [2A]
     
    • as neoadjuvant or adjuvant therapy, or chemotherapy alone for resectable disease
    • for locoregional unresectable or metastatic disease
       
  • Pheochromocytoma/Paraganglioma - Primary treatment as a single agent for distant metastases [2A]

  • Primary Cutaneous Lymphomas - Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders [2A]

    • Therapy for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions, or cutaneous ALCL with regional nodes (excludes systemic ALCL), as a single agent for relapsed/refractory disease with CNS involvement

  • Mycosis Fungoides (MF)/Sezary Syndrome (SS) - Systemic therapy as treatment for CNS involvement with [2B for relapsed or persistent stage IA-IIA MF with B1 blood involvement; 2A for others]

    • relapsed or persistent stage IA mycosis fungoides (MF) with B1 blood involvement, with or without skin-directed therapy
    • relapsed or persistent stage IB-IIA MF with B1 blood involvement, with or without skin-directed therapy
    • stage IIB MF with limited tumor lesions refractory to multiple previous therapies, with or without skin-directed therapy
    • relapsed or refractory stage IIB MF with generalized tumor lesions, with or without skin-directed therapies
    • stage IIB MF with generalized tumor lesions that is refractory to multiple previous therapies or progression
    • relapsed or persistent stage III MF, with or without skin-directed therapies
    • stage III MF that is refractory to multiple previous therapies
    • relapsed or persistent stage IV Sezary syndrome
    • relapsed or persistent stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control
    • large cell transformation (LCT) with limited cutaneous lesions that is refractory to multiple previous therapies
    • relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy
       
  • Small cell lung cancer - Subsequent chemotherapy for patients with performance status 0-2 as a single agent for [2A]
     
    • relapse within 6 months following complete or partial response or stable disease with initial treatment
    • primary progressive disease 

  • Soft Tissue Sarcoma - Solitary Fibrous Tumor/Hemangiopericytoma  - In combination with bevacizumab for the treatment of solitary fibrous tumor and hemangiopericytoma [2A]
  • Soft Tissue Sarcoma Extremity/Superficial Trunk, Head/Neck - Single-agent palliative chemotherapy for synchronous stage IV or recurrent disease with disseminated metastases [2A]
  • Soft Tissue Sarcoma - Retroperitoneal/Intra-abdominal - Single-agent palliative chemotherapy for unresectable or progressive disease [2A]
  • Soft Tissue Sarcoma - Rhabdomyosarcoma - Therapy for [2A]

    • pleomorphic rhabdomyosarcoma as single-agent palliative therapy
    • nonpleomorphic rhabdomyosarcoma in combination with vincristine and irinotecan

  • Soft Tissue Sarcoma - Angiosarcoma - Single-agent palliative therapy for angiosarcoma [2A]
  • Uveal melanoma - Consider as single agent therapy distant metastatic disease [2A] 
  • Uterine Sarcoma - Consider as single-agent therapy for recurrent or metastatic disease which has progressed following prior cytotoxic chemotherapy [2B for Stage I disease; 2A for all others].
Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

96413 Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
96415 Chemotherapy administration, intravenous infusion technique; each additional hour (list separately in addition to code for primary procedure)

HCPCS codes covered if selection criteria are met:

J9328 Injection, temozolomide 1 mg

Other HCPCS codes related to the CPB:

J1930 Injection, lanreotide, 1 mg
J2353 Injection, octreotide, depot form for intramuscular injection, 1 mg
J2354 Injection, octreotide, non-depot form for subcutaneous or intravenous injection, 25 mcg
J8520 Capecitabine, oral, 150 mg
J8521 Capecitabine, oral, 500 mg
J8610 Methotrexate; oral, 2.5 mg
J8700 Temozolomide, oral, 1 mg
J9035 Injection, bevacizumab, 10 mg
J9050 Injection, carmustine, 100 mg
J9206 Injection, irinotecan, 20 mg
J9250 Methotrexate sodium, 5 mg.
J9260 Methotrexate sodium, 50 mg
J9370 Vincristine sulfate, 1 mg
J9371 Injection, vincristine sulfate liposome, 1 mg
Q5107 Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg

ICD-10 codes covered if selection criteria are met:

C25.0, C25.2, C25.4, C25.9 Malignant neoplasms of pancreas [neuroendocrine tumors of the pancreas (islet cell tumors)]
C33 - C34.92 Malignant neoplasm of trachea, broncus, and lung [small cell lung cancer (SCLC)]
C40.00 - C41.9 Malignant neoplasm of bone and articular cartilage [Ewing's sarcoma family of tumors] [spinal ependymoma]
C43.0 - C43.9 Malignant melanoma of skin [cutaneous melanoma - metastatic or unresectable]
C44.90 Malignant neoplasm of skin [metastatic dermatofibrosarcoma protuberans]
C48.0 - C48.8 Malignant neoplasm of retroperitoneum and peritoneum
C49.0 - C49.9 Malignant neoplasm of other connective and soft tissue
C53.0 - C53.9, C55 Malignant neoplasm of uterus, part unspecified and cervix uteri [uterine sarcoma]
C54.0 - C54.9 Malignant neoplasm of corpus uteri [uterine sarcoma]
C69.30 - C69.32 Malignant neoplasm of choroid [uveal melanoma - distant metastatic]
C69.40 - C69.42 Malignant neoplasm of ciliary body [uveal melanoma - distant metastatic]
C69.90 - C69.92 Malignant neoplasm of eyeball [uveal melanoma - distant metastatic]
C71.0 - C71.9 Malignant neoplasm of brain [intracranial ependymoma] [adult low-grade infiltrative supratentorial astrocytoma/oligodendroglioma] [adult medulloblastoma or supratentorial primitive neuroectodermal tumors (PNET)] [anaplastic gliomas] [glioblastoma]
C72.0 - C72.9 Malignant neoplasm of central nervous system [anaplastic gliomas, glioblastoma, adult low-grade infiltrative supratentorial astrocytoma/oligodendroglioma (excluding pilocytic astrocytoma)]
C7A.00 - C7A.029, C7A.091 - C7A.8 Malignant neuroendocrine tumors
C7A.090 Malignant carcinoid tumors of the bronchus and lung [lung neuroendocrine tumors]
C74.00 - C74.92 Malignant neoplasm of adrenal gland
C75.5 Malignant neoplasm of aortic body and other paraganglia
C79.31 Secondary malignant neoplasm of brain [limited (1-3) metastatic lesions, multiple (>3) metastatic lesions, melanoma, small cell lung cancer (SCLC)]
C83.80, C83.81, C83.89 Other non-follicular lymphoma, head, face, and neck, and extranodal and solid organ sites [primary CNS lymphoma]
C84.00 - C84.19 Mycosis fungoides and Sezary's disease
C84.60 - C84.69 Anaplastic large cell lymphoma, ALK-positive
C84.70 - C84.79 Anaplastic large cell lymphoma, ALK-negative
D13.7 Benign neoplasm of endocrine pancreas [Benign neoplasm of islets of Langerhans] [Islet cell tumors]
D43.0 - D43.2, D43.4 Neoplasm of uncertain behavior of brain and spinal cord [adult low-grade infiltrative supratentorial astrocytoma/oligodendroglioma (excluding pilocytic astrocytoma)]

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

C18.0 - C18.9 Malignant neoplasm of colon
C19 Malignant neoplasm of rectosigmoid junction
C47.0 - C47.9 Malignant neoplasm of peripheral nerves and autonomic nervous system [not covered for myxopapillary ependymomas and neuroblastoma]
C72.0 - C72.9 Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system [not covered for myxopapillary ependymomas and neuroblastoma]
C75.1 Malignant neoplasm of pituitary gland
C83.30 - C83.39 Diffuse large B-cell lymphoma
C91.10 - C91.12 Chronic lymphocytic leukemia of B-cell type
D35.2 Benign neoplasm of pituitary gland
D48.5 Neoplasm of uncertain behavior of skin [dermatofibroma protuberans]

The above policy is based on the following references:

  1. Almalki MH, Aljoaib NN, Alotaibi MJ, et al. Temozolomide therapy for resistant prolactin-secreting pituitary adenomas and carcinomas: A systematic review. Hormones (Athens). 2017;16(2):139-149.
  2. Aydogan Bİ, Unluturk U, Emral R, Gullu S. Course of aggressive somatotroph, corticotroph and mammotroph tumors under temozolomide. Report of three cases and review of the literature. Turk Neurosurg. 2018;29(5). 
  3. Back MF, et al. Improved median survival for glioblastoma multiforme following introduction of adjuvant temozolomide chemotherapy. Ann Acad Med Singapore. 2007;36(5):338-335.
  4. Barkhoudarian G, Palejwala SK, Ogunbameru R, et al. Early recognition and initiation of temozolomide chemotherapy for refractory, invasive pituitary macroprolactinoma with long-term sustained remission: A case report. World Neurosurg. 2018;118:118-124.
  5. Cencini E, Fabbri A, Arrigucci U, et al. Lenalidomide and temozolomide combination in a very elderly patient with CNS relapse of diffuse large B-cell lymphoma. Mediterr J Hematol Infect Dis. 2017;9(1):e2017040.
  6. Chen L, Pastorino F, Berry P, et al. Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma. Int J Cancer. 2019;144(12):3146-3159. 
  7. Dubois SG, Mosse YP, Fox E, et al. Phase 2 trial of alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma. Clin Cancer Res. 2018;24(24):6142-6149.
  8. Fujiwara Y, Manabe H, Izumi B, et al. Remarkable efficacy of temozolomide for relapsed spinal myxopapillary ependymoma with multiple recurrence and cerebrospinal dissemination: A case report and literature review. Eur Spine J. 2018;27(Suppl 3):421-425.
  9. Gilis-Januszewska A, Wilusz M, Pantofliński J, et al. Temozolomide therapy for aggressive pituitary Crooke's cell corticotropinoma causing Cushing's Disease - a case report with literature review. Endokrynol Pol. 2018;69(3):306-312.
  10. Gramatzki D, Kickingereder P, Hentschel B, et al. Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma. Neurology. 2017;88(15):1422-1430.
  11. Merck Sharpe and Dohme Corp. Temodar (temozolomide) capsules. Temodar (temozolomide) for Injection administered via intravenous infusion. Prescribing Information. Whitehouse Station, NJ: Merck & Company, Inc.; revised October 2017.
  12. Merck Sharpe and Dohme Corp. Temodar (temozolomide) capsules. Temodar (temozolomide) for Injection administered via intravenous infusion. Prescribing Information. Whitehouse Station, NJ: Merck & Company, Inc.; revised November 2019.
  13. National Comprehensive Cancer Network (NCCN). Temozolomide. NCCN Drug and Biologics Compendium. Fort Washington, PA: NCCN; 2019.
  14. National Comprehensive Cancer Network (NCCN). Temozolomide. NCCN Drug and Biologics Compendium. Fort Washington, PA: NCCN; 2020.
  15. National Comprehensive Cancer Network (NCCN). Central nervous system cancers. NCCN Clinical Practice Guidelines in Oncology, version 2.2018. Fort Washington, PA: NCCN; 2019.
  16. National Comprehensive Cancer Network (NCCN). Central nervous system cancers. NCCN Clinical Practice Guidelines in Oncology, version 3.2019. Fort Washington, PA: NCCN; 2020.
  17. National Comprehensive Cancer Network (NCCN). Neuroendocrine and adrenal tumors. NCCN Clinical Practice Guidelines in Oncology, version 4.2018. Fort Washington, PA: NCCN; 2019
  18. National Comprehensive Cancer Network (NCCN). Soft tissue sarcoma. NCCN Clinical Practice Guidelines in Oncology, version 1.2019. Fort Washington, PA: NCCN; 2019
  19. Pishvaian MJ, Slack RS, Jiang W, et al. A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer. Cancer. 2018;124(11):2337-2346.
  20. Rao A, Ramani N, Stoppacher R, Coyle T. Complete response to temozolomide in chronic lymphocytic leukemia. Clin Case Rep. 2017;5(7):1130-1131.
  21. Synder PJ. Management of hyperprolactinemia. UpToDate Inc., Waltham, MA. Last reviewed July 2018.
  22. Syro LV, Rotondo F, Camargo M, et al. Temozolomide and pituitary tumors: Current understanding, unresolved issues, and future directions. Front Endocrinol (Lausanne). 2018;9:318.
  23. Xin Y, Guo W, Yang CS, et al. Meta-analysis of whole-brain radiotherapy plus temozolomide compared with whole-brain radiotherapy for the treatment of brain metastases from non-small-cell lung cancer. Cancer Med. 2018;7(4):981-990.